Objective To investigate the protective effect of methotrexate on probable rheumatoid arthritis (RA) patients. Methods 62 probable rheumatoid arthritis (RA) patients were randomly divided into two groups, treatment group (32 cases) accepted methotrexate and non-steroidal anti-inflammatory drug and control group only non-steroidal anti-inflammatory drug. In the 2-year follow-up visit, patients who developed to RA would withdraw and accept normal combined medicine treatment. They were assessed with X-ray changes of the hand joints. Results 8 cases of the treatment group developed RA (2 cases withdrew because of intolerance), while 17 cases of the control group developed RA. The treatment group developed RA later than the control group, with less radiographic joints injury in 2 years. Conclusion Methotrexate can delay clinical process of the development of RA in the probable RA patients and reduce joints damage.