Low-dose methotrexate, the kind prescribed weekly for rheumatoid arthritis or psoriasis, carries a small increased risk for certain cancers, particularly some skin cancers and a rare type of lymphoma. But the overall risk is modest, and separating the drug’s effect from the underlying disease is one of the biggest challenges in this research. For most people, the benefits of controlling chronic inflammation likely outweigh the added cancer risk.
How Methotrexate Could Affect Cancer Risk
Methotrexate at low doses works by dialing down your immune system’s overactivity. That’s what makes it effective against autoimmune conditions, but it also reduces your body’s ability to detect and destroy abnormal cells before they become cancerous. Specifically, it decreases antibody production, slows the movement of immune cells toward threats, and reduces the signaling molecules that coordinate immune responses. This weakened “immune surveillance” is the main theoretical pathway by which methotrexate could allow certain cancers to develop.
There’s an important flip side, though. Chronic inflammation itself drives cancer. Persistent inflammatory signals can rewire cellular metabolism and create conditions that favor tumor growth. By suppressing that inflammation, methotrexate may actually reduce the cancer-promoting environment that autoimmune diseases create. This dual nature makes it genuinely difficult to determine whether the drug increases or decreases overall cancer risk in any given patient.
Skin Cancer: The Clearest Signal
Skin cancers show the strongest and most consistent association with methotrexate use. A nationwide case-control study published in the British Journal of Cancer found that cumulative methotrexate doses of 2.5 grams or more (which corresponds to years of weekly use) were associated with a 61% higher risk of squamous cell carcinoma and a 29% higher risk of basal cell carcinoma compared to people who never used the drug. Squamous cell carcinoma carries the larger increase, which is notable because it’s also the more aggressive of the two common skin cancers.
For melanoma, the picture is more nuanced. A systematic review and meta-analysis in JAMA Dermatology pooled data from multiple studies and found a 15% increased risk of melanoma in people exposed to methotrexate. That’s statistically significant but small in absolute terms, since melanoma is a rare cancer to begin with. When the researchers removed the single largest study from the analysis to test whether it was skewing results, the association dropped to borderline significance. So the melanoma link exists but is not as robust as the squamous cell carcinoma finding.
If you’re on long-term methotrexate, regular skin checks become more important. This is especially true if you have other skin cancer risk factors like fair skin, a history of sunburns, or significant sun exposure.
Lymphoma and Lymphoproliferative Disorders
Methotrexate-associated lymphoproliferative disorder is a recognized condition in which abnormal lymph tissue growths develop during treatment. It’s uncommon but well-documented, and it has a unique feature: these growths often regress when methotrexate is stopped. In a study of 35 rheumatoid arthritis patients who developed this condition, 66% saw their abnormal growths shrink or disappear after discontinuing the drug, without needing chemotherapy.
Many of these cases are linked to Epstein-Barr virus, the same virus that causes mono. In the same study, 44% of patients tested positive for the virus in their abnormal tissue. The connection was particularly strong in certain subtypes: 100% of Hodgkin-type cases were virus-positive. The relationship between viral infection and regression after stopping methotrexate was statistically significant, suggesting the drug may allow the virus to drive lymph cell overgrowth by suppressing the immune response that normally keeps it in check.
One complication: among the patients whose growths initially regressed, 56% later experienced relapse or regrowth. This means stopping methotrexate isn’t always a permanent fix, and some patients eventually need additional treatment.
Despite these case reports, large population studies haven’t found a clear overall increase in lymphoma risk from methotrexate. A 12-year population-based cohort study found no statistically significant difference in lymphoma rates between rheumatoid arthritis patients who took methotrexate and those who didn’t. Researchers have proposed that the elevated lymphoma risk seen in rheumatoid arthritis patients may be driven primarily by the chronic inflammation of the disease itself rather than by the medication.
The Underlying Disease Complicates Everything
This is the critical point that often gets lost in online discussions. Rheumatoid arthritis, psoriasis, and other conditions treated with methotrexate already carry their own independent cancer risks. Chronic, systemic inflammation promotes tumor development through multiple pathways. So when a study finds higher cancer rates among methotrexate users, it’s hard to know how much of that increase comes from the drug and how much comes from the disease the drug is treating.
A large national claims database study published in The Lancet Regional Health explored this question by comparing cancer risk in rheumatoid arthritis patients to the general population. When the researchers broadened their analysis to include all rheumatoid arthritis patients regardless of treatment, the overall cancer risk moved closer to that of the general population. This suggests that the disease itself, not just its treatment, plays a significant role in any observed cancer risk. Interestingly, some cancers were actually less common in the rheumatoid arthritis population. Breast cancer rates were lower, possibly because hormonal factors associated with the disease (like earlier menopause) happen to be protective against breast cancer.
Does Cumulative Dose Matter?
You might expect that higher total lifetime doses of methotrexate would mean higher cancer risk, and for skin cancer, the evidence supports that pattern. The increased risks for squamous cell carcinoma and basal cell carcinoma were specifically found at cumulative doses of 2.5 grams or more.
For other cancers, the dose-risk relationship is less straightforward. One large Taiwanese cohort study actually suggested that middle and high cumulative doses of methotrexate might be associated with lower overall cancer risk in rheumatoid arthritis patients, possibly because better disease control reduced inflammation-driven cancer development. This counterintuitive finding hasn’t been replicated widely enough to be definitive, but it reinforces the idea that the relationship between methotrexate and cancer is not a simple “more drug equals more risk” equation.
Putting the Risk in Perspective
The cancer risks associated with low-dose methotrexate are real but generally small. A 15% relative increase in melanoma risk, for example, means that if your baseline annual risk of melanoma is roughly 1 in 5,000, methotrexate might shift that to about 1.15 in 5,000. Squamous cell carcinoma shows a larger relative increase, but the absolute numbers remain modest for most patients.
The lymphoproliferative disorder risk is the most clinically dramatic, but it’s rare and often reversible. And the question of whether methotrexate’s anti-inflammatory benefits might actually protect against some inflammation-driven cancers remains open. For most people taking weekly low-dose methotrexate for an autoimmune condition, the benefits of controlling a disease that would otherwise damage joints, skin, or organs tend to outweigh these modest increases in cancer risk. Staying current with routine cancer screenings and paying attention to skin changes are practical steps that address the known risks without requiring you to stop an effective treatment.