Hydroxychloroquine is generally considered the safer of the two drugs. It requires less routine blood work, carries a lower risk of organ damage, and is even safe to use during pregnancy. Methotrexate is more potent but comes with a heavier monitoring burden and a wider range of potentially serious side effects, including liver damage, bone marrow suppression, and a small increase in infection risk.
Both medications are commonly prescribed for rheumatoid arthritis and lupus, and both have decades of safety data behind them. But they sit in very different places on the risk spectrum, which is why the choice between them often depends on how aggressive the disease is and what trade-offs you’re willing to accept.
Day-to-Day Side Effects
The most common complaint with both drugs is nausea. About 11.7% of people on hydroxychloroquine experience it, compared to 14.9% on methotrexate. That difference is modest, but it understates how differently these drugs feel in daily life. Methotrexate is taken once a week (usually by mouth, sometimes by injection), and many people describe a “methotrexate hangover” the day after their dose: fatigue, brain fog, and stomach upset that can linger for 24 to 48 hours. Adding a weekly folic acid supplement (typically 1 mg daily or 5 mg once a week) reduces these symptoms significantly, and most rheumatologists prescribe it alongside methotrexate as standard practice.
Hydroxychloroquine is taken daily, and its gastrointestinal effects tend to be milder and more constant rather than hitting in a wave. Most people tolerate it well enough that side effects don’t interfere with their routine.
Liver and Blood Monitoring
This is where the safety gap widens considerably. Methotrexate can damage the liver over time, potentially leading to fibrosis or scarring. To catch problems early, you’ll need regular blood draws: a complete blood count seven days after starting or increasing your dose, then every two to four weeks for the first few months, and every one to three months after that. If liver enzyme levels stay elevated on repeated tests, your doctor may pause the medication or, in some cases, recommend a liver biopsy.
Methotrexate also suppresses bone marrow function, which means it can lower your white blood cell count, red blood cell count, or platelet count. Roughly 3% to 4% of rheumatoid arthritis patients on methotrexate develop low platelets, and drops in white blood cells can appear within one to three weeks of starting treatment. These changes are usually caught through routine blood work, but they require ongoing vigilance.
Hydroxychloroquine, by contrast, does not require regular blood tests for liver or bone marrow monitoring. It doesn’t cause the kind of organ-level toxicity that demands frequent lab checks, which is one reason many patients and doctors view it as the easier drug to live with.
Eye Health With Hydroxychloroquine
The signature long-term risk of hydroxychloroquine is retinal toxicity. The drug can accumulate in the retina over years and, in rare cases, cause permanent vision changes. According to the American Academy of Ophthalmology, the likelihood of toxicity within the first five years is below 1% when the dose stays at or under 5 mg per kilogram of body weight per day. Even after 10 years of use, the risk stays below 2%.
You’ll need a baseline eye exam (including imaging of the retina) soon after starting the drug. If you have no major risk factors, annual eye screening can be deferred for the first five years, but it should begin reliably after that point. If risk factors are present, such as kidney disease or higher dosing, annual screening starts right away. The damage, if caught early through screening, can be stopped by discontinuing the medication, but it isn’t reversible once it progresses.
Heart Rhythm Concerns
Hydroxychloroquine can affect the heart’s electrical system by prolonging a measurement on an EKG called the QT interval. In one study of rheumatoid arthritis patients, hydroxychloroquine alone was associated with an average QT increase of 18 milliseconds. Long-term use has also been linked to rare cases of cardiomyopathy (weakening of the heart muscle) and conduction abnormalities.
In practice, serious heart rhythm events like torsades de pointes (a dangerous type of arrhythmia) are rare. A large analysis of over 5,600 patients found the pooled incidence of serious arrhythmia or cardiac arrest was about 3 per 1,000, and that data came largely from COVID-era studies where patients were often already critically ill. Among lupus patients on long-term hydroxychloroquine, severe QT prolongation was rare and no serious arrhythmias were observed.
The risk increases when hydroxychloroquine is combined with other drugs that affect the QT interval. Twelve medications have been specifically flagged for this interaction, including common ones like tramadol, clarithromycin, diltiazem, and cyclosporine. Many of these drugs slow the breakdown of hydroxychloroquine in the body, raising its concentration and amplifying the cardiac effect.
Infection Risk
Hydroxychloroquine is not thought to increase infection risk at all. Methotrexate suppresses parts of the immune system more aggressively, and the data on infections reflects that. A large trial of over 9,300 patients found that methotrexate caused a modest increase in general infections compared to placebo (16.5 versus 14.4 per 100 person-years), though the rate of serious infections was essentially the same between the two groups. The overall picture: methotrexate slightly raises your chance of common infections like colds or urinary tract infections, but it does not appear to meaningfully increase the risk of severe or life-threatening ones.
Pregnancy Safety
This is one of the starkest differences between the two drugs. Methotrexate is strictly contraindicated in pregnancy. It can cause miscarriage and serious birth defects, and both men and women are typically advised to stop the drug months before trying to conceive.
Hydroxychloroquine is not only considered safe during pregnancy but is actively recommended. The Society for Maternal-Fetal Medicine advises that pregnant people with lupus should continue or even start hydroxychloroquine. Studies have found no increased chance of birth defects, preterm delivery, or low birth weight. For anyone planning a pregnancy, this distinction alone often determines which drug is the better choice.
How They Compare Overall
Hydroxychloroquine is the milder drug in almost every dimension: fewer side effects, less monitoring, no immune suppression, safe in pregnancy. Its main long-term concern, retinal toxicity, is rare and manageable with regular eye exams. Methotrexate demands more from you in terms of blood work and lifestyle adjustments, and it carries real risks to the liver, bone marrow, and developing fetus. But methotrexate is also substantially more effective at controlling aggressive inflammatory disease, which is why it remains the first-line treatment for moderate to severe rheumatoid arthritis.
The two drugs are often not interchangeable in practice. Hydroxychloroquine works well for milder disease and is frequently used in lupus, while methotrexate is reserved for situations where stronger disease control is needed. Many people end up taking both together, since hydroxychloroquine’s favorable safety profile makes it easy to add to a treatment regimen without significantly increasing risk. The “safer” drug isn’t always the right drug, but when disease severity allows a choice, hydroxychloroquine places a lighter burden on the body.