Iguratimod (IGU) has been suggested to be a novel and useful DMARD with a unique mechanism of action. It is much less expensive than biologics. We evaluated and compared the efficacy and safety of IGU, methotrexate (MTX), and IGU+MTX for the treatment of rheumatoid arthritis (RA). RA patients were randomly divided into three groups: IGU+MTX, placebo+IGU and placebo+MTX group. Relevant laboratory parameters were periodically reviewed and clinical outcome measures were assessed after 4, 8, 12, 16 and 24 weeks. Symptoms of all patients significantly improved after treatment. After four weeks of treatment, differences in American College of Rheumatology 20% improvement criteria response rate (ACR20) between any of the groups were not significant. However, ACR20 response rate improved more in the MTX+IGU group compared to the monotherapy groups. After 24 weeks of treatment, combined treatment with IGU and MTX was superior to monotherapy with either IGU or MTX. There were no significant differences between the incidences of adverse effects among the three treatment groups. In conclusion: The treatment of RA with IGU is effective, and the effect of IGU treatment becomes apparent earlier than MTX treatment. To some extent, the combination of IGU and MTX results in an additive therapeutic effect. IGU+MTX maybe used as first-line treatment instead of MTX.