One hundred and one patients with rheumatoid arthritis were followed prospectively to assess the efficacy and toxicity of therapy with D-penicillamine. After a mean total followup of 11.5 months (38 patients have completed 2 years of followup) there was a 70% overall improvement rate with 2 complete remissions. Sixty-one patients developed 84 separate toxic reactions, 36 of which required drug withdrawal. Skin rashes (27/84), proteinuria (15/84), low platelets (14/84), and taste abnormalities (10/84) were the most common side effects of therapy at a mean D-penicillamine dose of 463 mg/day. The majority of toxic reactions (85%) occurred in the first 6 months, but proteinuria and thrombocytopenia were more common in the 6 to 12 month treatment period. Previous gold toxicity was a risk factor for developing D-penicillamine toxicity (10/13). Our observations suggest that D-penicillamine related toxicity is a major problem even at 500 mg/day, but the drug can be used with an increased safety margin after 9 months of continuous therapy.