The accumulated evidence from years of research shows that common NSAIDs like ibuprofen and naproxen do not worsen COVID-19 outcomes, despite alarming warnings that circulated early in the pandemic. Multiple large cohort studies and clinical trials have consistently found no increased risk of death, hospitalization, or disease severity in COVID-19 patients who used these drugs. The path from early panic to that reassuring conclusion involved some genuinely interesting science along the way.
How the Scare Started
In March 2020, France’s Minister of Health publicly advised against using ibuprofen and other NSAIDs in patients with COVID-19, warning that these drugs might worsen the infection.1PubMed Central. Does Ibuprofen Worsen COVID-19? The warning spread rapidly across social media worldwide and created considerable anxiety among patients and doctors alike. People who routinely took ibuprofen for headaches, menstrual cramps, or arthritis suddenly weren’t sure whether the pills in their medicine cabinet could put them at greater risk from a virus nobody fully understood yet.
The concern wasn’t entirely baseless. It grew from a letter published in The Lancet suggesting that NSAIDs might increase levels of a protein called ACE2, which the SARS-CoV-2 virus uses as its entry point into human cells. The idea seemed logical on the surface: if NSAIDs make more doors available for the virus to walk through, they could make infection easier or worse. But the hypothesis rested on thin evidence, and researchers immediately began testing it.
The ACE2 Theory and Why It Collapsed
The original worry about NSAIDs and ACE2 traced back to a single study in diabetic mice. That study had found that one particular drug increased ACE2 expression, and some researchers extrapolated this to suggest that ibuprofen and similar drugs might do the same in humans, potentially helping the coronavirus invade more cells. A narrative review published in 2023 traced the fate of this idea through the studies that followed and found it thoroughly debunked.2PubMed Central. Ibuprofen, other NSAIDs and COVID-19: a narrative review
Multiple research groups tested whether NSAIDs actually affect ACE2 activity in lab settings and in living organisms. The results consistently showed no harmful effect on ACE2 from the NSAIDs tested or from acetaminophen (paracetamol). One team did find that ibuprofen could increase ACE2 levels, but with a twist: ibuprofen simultaneously blocked two other proteins that the virus needs to get inside cells, which meant the net effect actually reduced viral entry rather than increasing it.3PubMed Central. Ibuprofen, other NSAIDs and COVID-19: a narrative review More ACE2 on the cell surface, it turned out, doesn’t automatically translate into more virus getting in. The whole theoretical chain from the French minister’s warning had come apart.
Do NSAIDs Raise Your Chances of Catching COVID?
One of the first practical questions researchers tackled was whether people who regularly take NSAIDs are more likely to test positive for SARS-CoV-2 in the first place. Several large studies addressed this, and the answer was consistently no.
A study of over 2,100 patients at a Barcelona rheumatology clinic found no link between chronic NSAID use and COVID-19 infection rates. An even larger analysis used data from 2.74 million users of a COVID symptom-tracking smartphone app across the US, UK, and Sweden. Initially, NSAID users appeared to have a modestly higher chance of testing positive, but that association disappeared entirely once researchers accounted for confounding factors like lifestyle and underlying health conditions. A UK primary care study comparing over 25,000 adults with osteoarthritis who were prescribed NSAIDs against those prescribed other painkillers likewise found no increased risk of infection or death.4PubMed Central. The use of non-steroidal anti-inflammatory drugs (NSAIDs) in COVID-19
That pattern of initial signals vanishing after proper adjustment showed up repeatedly in the literature. People who take NSAIDs regularly tend to be older, have more chronic conditions, and differ from non-users in ways that affect COVID-19 risk independently of the drugs themselves. Once you control for those differences, the apparent link between NSAID use and infection evaporates.
What Happens When NSAID Users Get Hospitalized
The more pressing concern was always whether NSAIDs affect how sick you get once infected. If these drugs suppress part of the immune response while you’re fighting a respiratory virus, you might expect worse outcomes. Fortunately, the evidence here is about as reassuring as observational data gets.
One of the most robust studies came from the ISARIC consortium in the UK, which tracked hospitalized COVID-19 patients and compared those who had been using NSAIDs against those who hadn’t. After adjusting for relevant variables, NSAID use showed no association with in-hospital death, admission to critical care, the need for mechanical ventilation, the need for supplemental oxygen, or the development of acute kidney injury.5The Lancet Rheumatology. Non-steroidal anti-inflammatory drug use and outcomes of COVID-19 in the ISARIC Clinical Characterisation Protocol UK cohort The matched odds ratios for all of those outcomes hovered right around 1.0, meaning NSAID users fared essentially the same as non-users.
A prospective cohort study of Saudi Arabian adults reached the same conclusion: acute or chronic NSAID use was not associated with worse COVID-19 outcomes across a range of measures including death, hospital admission, disease severity, time to improvement, and length of stay. A Danish nationwide cohort study echoed these findings, showing no link between NSAID prescriptions filled up to 30 days before a positive test and 30-day mortality, hospitalization, ICU admission, or the need for mechanical ventilation.6PubMed Central. The use of non-steroidal anti-inflammatory drugs (NSAIDs) in COVID-19
Looking at ibuprofen specifically, an Israeli study of hospitalized COVID-19 patients found mortality rates of about 3.4% in the ibuprofen group versus 2.8% in the non-ibuprofen group, a difference that was not statistically significant. Rates of needing respiratory support were similarly indistinguishable between groups.7PubMed Central. Ibuprofen use and clinical outcomes in COVID-19 patients A nationwide Danish register-based study also found no meaningful difference, with standardized risk ratios for severe outcomes in ibuprofen-prescribed patients sitting at 0.96 compared with non-users.8PubMed Central. Association Between Prescribed Ibuprofen and Severe COVID-19 Infection: A Nationwide Register-Based Cohort Study
A large 38-center retrospective study in the US used propensity matching to construct groups of nearly 20,000 COVID-19 inpatients each, treated and untreated with NSAIDs, drawn from over 857,000 patients in a national database.9PubMed Central. NSAID use and clinical outcomes in COVID-19 patients: a 38-center retrospective cohort study The scale of that dataset alone speaks to how seriously the research community took the original concern, and the findings kept pointing in the same direction: no worse outcomes.
Could Some NSAIDs Actually Help Fight COVID?
While most of the research effort went into proving NSAIDs weren’t harmful, a smaller but intriguing line of investigation asked whether certain NSAIDs might actively help. This is where the science gets genuinely surprising.
Lab experiments found that certain NSAIDs can reduce SARS-CoV-2 replication in cell cultures. When indomethacin was combined with the antihistamine ketotifen, viral inhibition reached 93% at the highest concentration tested. Naproxen combined with ketotifen showed a similar pattern, reaching 92% inhibition.10PubMed Central. In Vitro Assessment of the Antiviral Activity of Ketotifen, Indomethacin and Naproxen, Alone and in Combination, against SARS-CoV-2 These are lab results, not clinical outcomes, but they suggested a biological mechanism worth exploring.
An open-label randomized trial in India tested indomethacin head-to-head against paracetamol in hospitalized COVID-19 patients. The results were striking: none of the 103 patients in the indomethacin group developed drops in oxygen saturation, while 20 out of 107 in the paracetamol group did. Patients on indomethacin also saw faster symptom relief, with most symptoms resolving in half the time.11PubMed Central. An open label randomized clinical trial of Indomethacin for mild and moderate hospitalised Covid-19 patients An earlier preprint from a different group had reported similar trends, with only 1 out of 72 indomethacin-treated patients needing supplemental oxygen versus 28 of 72 in the paracetamol arm.12medRxiv. Efficacy and Safety of Indomethacin in Covid-19 patients
Before anyone runs to the pharmacy, though, these findings haven’t been universally replicated. Another randomized trial found that oral indomethacin did not reduce the need for intubation, did not shorten recovery time, and did not improve oxygen saturation levels, leading the authors to advise against recommending it for COVID-19 patients.13Immunopathologia Persa. Efficacy of oral indomethacin in the treatment of COVID-19 infection; a randomized clinical trial The positive trials were open-label, meaning participants knew which drug they were getting, which can bias results. Indomethacin is also a more potent and less commonly used NSAID with a rougher side-effect profile than ibuprofen, so even positive results wouldn’t necessarily translate into widespread recommendations.
The COX-2 Inhibitor Question
Separate from the general NSAID story, selective COX-2 inhibitors like celecoxib have attracted their own research attention. These drugs target a narrower part of the inflammatory pathway than traditional NSAIDs do, and some researchers hypothesized this selectivity might offer advantages against COVID-19’s characteristic overblown inflammatory response.
A review of the literature argued that COX-2 and its downstream inflammatory signals play central roles in coronavirus-related cell death and the dangerous “cytokine storm” that drives severe COVID-19 cases, making targeted COX-2 inhibition a plausible treatment strategy.14PubMed Central. COX2 inhibition in the treatment of COVID-19: Review of literature to propose repositioning of celecoxib for randomized controlled studies A randomized trial of celecoxib in hospitalized patients reportedly reduced systemic inflammation and improved lung imaging, and a combination of celecoxib with high-dose famotidine was linked to improved clinical outcomes.15Heliyon. Non-steroidal anti-inflammatory drugs and viral/bacterial infections: A comprehensive review
A 2024 real-world data study suggested that selective COX-2 inhibitors might reduce the risk of disease progression in patients who tested positive, though the authors framed this as a finding that warrants further investigation rather than a treatment recommendation.16PubMed Central. The role of traditional NSAIDs and selective COX-2 inhibitors on COVID-19 outcomes: a real-world data study The evidence here is still preliminary. None of these findings have led to changes in treatment guidelines, and COX-2 inhibitors carry their own cardiovascular risks that would need to be weighed against any COVID-19 benefit.
Taking NSAIDs Around COVID Vaccination
A common worry during vaccine rollouts was whether popping an ibuprofen before or after your shot would blunt the immune response. Many people wanted pain relief from the sore arm, fatigue, and fever that mRNA vaccines in particular were known for, but worried they’d be undermining the very protection they were lining up to get.
Multiple studies have now addressed this, and the consensus is that analgesics taken around vaccination don’t reduce antibody responses. A study of people receiving BNT162b2 (Pfizer) boosters found no significant difference in antibody levels between those who took an antipyretic before vaccination and those who didn’t. The fold increase in antibodies was nearly identical in both groups.17PubMed Central. No significant influence of pre-vaccination antipyretic use on specific antibody response to a BNT162b2 vaccine booster against COVID-19
Data from the Oxford/AstraZeneca Phase 1/2 trial, where some sites permitted prophylactic acetaminophen, showed that taking pain relief before vaccination did reduce side effects like pain, chills, muscle aches, and headache, without affecting the immune response.18npj Vaccines. Use of analgesics/antipyretics in the management of symptoms associated with COVID-19 vaccination A larger analysis comparing over 2,300 vaccinated individuals found that people who took NSAIDs or acetaminophen after vaccination actually had somewhat higher antibody levels than those who took nothing, though this likely reflects the fact that people with stronger immune responses tend to feel worse and reach for a painkiller. When researchers matched participants by symptom severity, the antibody differences disappeared. The conclusion: no evidence that analgesic use reduces antibody responses.19ImmunoHorizons. No Evidence That Analgesic Use after COVID-19 Vaccination Negatively Impacts Antibody Responses
What About Children
Pediatric COVID-19 presented its own version of the NSAID dilemma. Ibuprofen is one of the most widely used fever reducers in children, and parents suddenly faced conflicting advice about whether to give it during a pandemic illness. A review focused specifically on the pediatric context found that no studies had been conducted on ibuprofen use in children with COVID-19. The authors noted that a causal link between ibuprofen and worse COVID outcomes had not been established in any population, but given the limited data and the generally milder course of COVID-19 in children, they suggested using acetaminophen as the first-line fever reducer for kids with confirmed SARS-CoV-2 infection.20PubMed Central. Serious infectious events and ibuprofen administration in pediatrics: a narrative review in the era of COVID-19 pandemic
That cautious recommendation was less about proven harm and more about the absence of pediatric-specific evidence. When no data exists for a particular group, defaulting to the safer-seeming option is standard medical practice, especially in children. As more time has passed without any signal of ibuprofen-related harm in pediatric COVID-19, this caution has largely softened in clinical practice, though no large pediatric trial has been published to settle the matter definitively.
NSAIDs and Long COVID
A newer and more complex question is whether NSAID use during acute COVID-19 might influence the risk of developing long COVID. A nationwide South Korean cohort study found an initial association: people who used NSAIDs within the first 14 days of a COVID-19 diagnosis appeared roughly 80% more likely to develop long COVID. However, that association became statistically non-significant once the researchers controlled for how long patients had been in self-quarantine, suggesting the link may reflect illness severity rather than a direct drug effect. People who are sicker during the acute phase are both more likely to take painkillers and more likely to develop lingering symptoms afterward.21PLOS ONE. Association between long COVID and nonsteroidal anti-inflammatory drug use by patients with acute-phase COVID-19
The same study found an interesting pattern in the opposite direction: NSAID use during the later, chronic phase of COVID-19 was associated with lower odds of long COVID. This might reflect the anti-inflammatory properties of NSAIDs dampening the sustained inflammation thought to drive many long COVID symptoms, though the authors stopped short of recommending NSAIDs as a preventive measure.
For people already experiencing long COVID, over-the-counter NSAIDs remain a reasonable option for managing joint and muscle pain during the post-acute period. A narrative review recommended NSAIDs for short-term relief of arthralgia and myalgia but cautioned that patients dealing with pain lasting several months should see a specialist rather than relying on long-term self-medication, given the well-known gastrointestinal and kidney risks of prolonged NSAID use.22PubMed Central. Long COVID Symptom Management Through Self-Care and Nonprescription Treatment Options: A Narrative Review
Blood Clots and the Theoretical Risk That Persists
One concern that hasn’t been fully resolved by the clinical data involves blood clotting. COVID-19 is known to increase the risk of blood clots, and NSAIDs have their own complicated relationship with coagulation. Non-aspirin NSAIDs can create an imbalance between two substances that regulate clotting, potentially tipping the balance toward a more clot-prone state. They also reduce levels of thrombomodulin, a protein that normally helps prevent clots.23Journal of Thrombosis and Haemostasis. Nonsteroidal anti‐inflammatory drugs and COVID‐19
This theoretical risk is worth understanding even though the large outcome studies didn’t find excess deaths or ICU admissions among NSAID users. Most of those studies measured broad outcomes like mortality and hospitalization rather than specifically tracking clotting events. For patients already at elevated risk of thrombosis, whether from severe COVID-19, immobility, or pre-existing conditions, the question of how NSAIDs interact with COVID-related coagulation changes hasn’t been answered as cleanly as the general safety question has. Aspirin, which is technically an NSAID but works quite differently on platelets, was studied separately as a potential anti-clotting treatment for COVID-19 and is a distinct conversation from the ibuprofen-and-naproxen story.
Why the Wrong Answer Stuck Around
Even years after the evidence settled, many people still believe NSAIDs are dangerous during COVID-19. Part of the reason is structural: the initial warning came from a government official and was amplified by social media at a moment of extreme fear, while the reassuring studies that followed trickled out across journals that most people never read. Corrections rarely travel as fast as the claims they’re correcting.
There’s also a subtlety in the evidence that feeds ongoing confusion. The large studies showing NSAIDs are safe mostly looked at people who were already taking them when they got infected. Those studies are good for answering “should I stop my NSAID if I get COVID?” (almost certainly no). They’re less informative about whether you should start taking an NSAID specifically to treat COVID symptoms if you weren’t already on one. Most health agencies have taken the position that both ibuprofen and acetaminophen are acceptable for managing fever and pain during COVID-19, and the choice between them should be guided by the same individual considerations that would apply for any respiratory illness: stomach sensitivity, kidney function, allergies, and personal preference.
The persistence of the myth has a real cost. People with chronic conditions like arthritis who stopped their NSAIDs out of fear may have experienced unnecessary pain or switched to alternatives with their own side effects. And the episode served as a case study in how a biologically plausible hypothesis, promoted at the right moment, can override the actual evidence for years afterward.