One hundred sixty-two consecutive patients with rheumatoid arthritis (RA) were studied for possible association between HLA antigens, particularly DR antigens, and disease characteristics and adverse reactions to gold or D-penicillamine treatment. The frequency of HLA-DR4 was significantly increased: 62% in RA compared to 23% in controls. An association of HLA-DR4 with a positive family history for RA was also found. HLA-DR4 was not associated with subcutaneous nodules or keratoconjunctivitis, presence of rheumatoid factor, or ANA positivity. No increased prevalence of HLA-DR3 was found in patients who developed drug related toxicity (e.g., proteinuria for gold or D-penicillamine). Of the 27 patients in whom proteinuria developed, only 5 were DR3 positive. A significant association with D-penicillamine induced proteinuria and HLA-B8 gene was found. Our results obtained in a systematic survey do not confirm previous reports of a significant association between HLA-DR3 and drug toxicity, but confirm the association between HLA-DR4 and the development of RA and HLA-B8 and D-penicillamine induced proteinuria.