AIM: To investigate the efficacy and safety of low-dose leflunomide (Lef) combined with methotrexate (MTX) in the treatment of rheumatoid arthritis (RA). METHODS: Sixty-four RA patients were randomly divided into two groups, with 32 patients in each group. All the patients were required to stop the treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) for 1 wk before entering the trial. Patients in the Lef+MTX group received Lef 20 mg, po, qd in the first 4 wk, followed by 10 mg,po, qd for next 20 wk. Patients also received MTX 7.5 mg,po, qw during the trial. Patients in the MTX group received MTX 15 mg,po, qw for 24 wk. Physical and laboratory examinations were performed at the beginning of the trial, after 12 wk treatment and 24 wk treatment. Entopic X-ray examination of both hands was performed before and after the treatment. RESULTS: The rate of remarkable improvement was 88% (28/32) in Lef+MTX group and 38% in MTX group (12/32). Adverse reactions were reported in 12% (4/32) patients in Lef+MTX group and 43% (14/32) patients in MTX group. The reported adverse reactions were rash and nausea in Lef+MTX group and nausea, vomiting, oral ulcer, alopecia, ALT elevation, palpitation and menoxenia in MTX group. CONCLUSION: Combination of Lef with MTX is safe and effective in treatment of RA with less adverse reactions.