Two hundred six patients were entered into a prospective controlled, double‐blind, multicenter trial comparing azathioprine (AZA) 1.25–1.5 mg/kg/day with D‐penicillamine (DP) 10–12 mg/kg/day. One hundred thirty‐four patients completed 24 weeks of therapy. Improvement in nearly all efficacy variables was seen in both groups. Patients taking DP demonstrated a greater rise in hemoglobin concentration and greater fall in erythrocyte sedimentation rate than patients receiving AZA; these were the only efficacy variables with a significant difference between the treatment groups. Fewer withdrawals for adverse reactions occurred among the patients receiving AZA, but the difference was not significant. Patients receiving AZA were withdrawn from the drug mainly for abnormal liver function test results, nausea and gastrointestinal upset, and leukopenia. The main reasons for withdrawal of patients receiving DP were nausea, rash and pruritis, thrombo‐cytopenia, dysgeusia, and proteinuria. Copyright © 1984 American College of Rheumatology