Background: We investigated whether taking methotrexate (MTX) is associated with a lower risk of new-onset cancers in patients with rheumatoid arthritis (RA). Methods: We conducted a 12-year retrospective cohort study from a population-based National Health Insurance Research Database in Taiwan. A total of 21,699 patients with newly diagnosed RA were enrolled during 2000–2009. The overall cancer rate was compared between 10,352 new users of MTX and 11,347 non-users. We used the WHO Defined Daily Dose (DDD) as a tool to assess drug exposure. Cox proportional hazard regression models were used to estimate the hazard ratio (HR) of disease after controlling for demographics and other comorbidities. Results: After adjusting for age, sex, cancer-related comorbidities, and RA-combined medication, the HR of cancer risk was 0.87 (95% CI = 0.74–1.02) for the MTX user group compared with the MTX non-user group. The cumulative incidence of cancer in the MTX non-user group was significantly higher than that of the MTX user group (log-rank test p < 0.001). In the low accumulative dose group [cumulative dose <1125 mg, cumulative defined daily dose (cDDD) <450], the HR of cancer risk for MTX users was 1.20 (95% CI = 1.01–1.42) compared with the MTX-non-user group. However, the adjusted HR of cancer risk was reduced to 0.66 (95% CI = 0.49–0.87) in MTX middle-dose users (cumulative dose 1125–2250 mg, cDDD: 450–899) and 0.33 (95% CI = 0.23–0.48) for the MTX high-dose group (cumulative dose ⩾2250 mg, cDDD ⩾900), respectively ( p for trend < 0.0001). Conclusion: MTX at middle and high accumulative doses might be associated with lower risk of new-onset cancers in patients with RA.