Thiopronin is a second line drug for rheumatoid arthritis with proven efficacy in controlled trials versus a placebo, D-penicillamine, or gold salts. This 4-month study was aimed mainly at comparing the efficacy and safety of two thiopronin regimens, i.e., 1 g/d for 2 weeks followed by 1.5 g/d (regimen A) versus 0.5 g/d for 1 month, 0.750 g/d during the second month, then 1 g/d (regimen B). Because earlier investigations have suggested a role for copper in the activity of D-penicillamine, a secondary goal of this study was to evaluate whether the clinical effects of thiopronin were related to changes in serum copper and ceruloplasmin levels. Among the 61 included patients, 32 received regimen A and 29 regimen B. The primary efficacy criterion was the physician's overall efficacy assessment. Efficacy was rated good or excellent in 65.5% of regimen A patients and 55.6% of regimen B patients. Eighteen of the 32 regimen A patients and 23 of the 29 regimen B patients experienced at least one adverse event (p = 0.055). Failure to tolerate the drug required withdrawal in 12 of the 32 regimen A patients (37.5%) versus 11 of the 29 regimen B patients (37.9%). Declines in serum copper and ceruloplasmin levels were not correlated with treatment efficacy or tolerance. These findings, together with previously reported data, suggest that treatment should be initiated in a dosage of 1 g/day and that thiopronin-related adverse events are not dose-dependent.