In order to compare the clinical effect and the frequency of side effect of D-penicillamine and bucillamine, we conducted a randomized, controlled clinical trial. Twenty-two and 24 patients were allocated to each section of the study, respectively. Bucillamine was at least as effective ad D-penicillamine in terms of improvement in the swollen joint count, tenderness score, morning stiffness, modified health assessment questionnaire, and Westergren erythrocyte sedimentation rate (ESR), and more effective in terms of improvement in the tender joint count, grip strength, C-reactive protein (CRP), and rheumatoid factor (RF) titer. In all, 27% of the bucillamine group and 33% of the D-penicillamine group responded; the response rate did not differ significantly between the two groups. The frequency of side effects tended to be lower in the bucillamine group. In conclusion, bucillamine was as effective as D-penicillamine in the treatment of rheumatoid arthritis, and with the former the frequency of side effects tended to be lower.