Background: This study assessed the efficacy and safety of methotrexate (MTX) compared with thiopurines (TPs) for refractory Crohn's disease. Methods: Fifty-one consecutive patients who were refractory or intolerant to TPs and steroid-dependent were retrospectively analyzed. MTX (20 mg/wk, subcutaneous) was adopted for inducing and maintaining clinical remission (CR). Fifty-seven patients who were naive to immunosuppressant and prescribed azathioprine (2 mg.kg(-1).d(-1)) or mercaptopurine (1 mg.kg(-1).d(-1)) were simultaneously recruited. Results: By week 16, the CR rate was 68.6% and 78.9% in the MTX and TPs groups, respectively (P = 0.222). Patients with disease duration <= 3 years were more likely to achieve CR with MTX (odds ratio = 7.667, P = 0.019). By week 64, the CR rate of patients achieved remission at week 16 was 45.7% and 44.4% in the MTX and TPs groups, respectively (P = 0.910). Normalization of high-sensitivity C-reactive protein level (relative risk = 11.221, P = 0.003) and platelet count (relative risk = 9.672, P = 0.004) at week 16 predicted the efficacy of maintaining remission with MTX. Among patients with remission at week 16, the mucosal healing rates at week 36 were 47.4% with MTX and 47.1% with TPs (P z 1.000). Fifteen (29.4%) patients on MTX and 25 (43.9%) on TPs experienced adverse events (P = 0.121). Conclusions: MTX is effective in inducing and maintaining CR and achieving mucosal healing in patients with refractory Crohn's disease, and its efficacy is comparable to that of TPs for naive patients. The side effects of MTX were mild and tolerable.