By means of a case-control study we investigated the association between HLA phenotypes and the development of proteinuria after aurothioglucose or D-penicillamine treatment in patients with rheumatoid arthritis (RA). HLA-DR3 was markedly increased in 44 treatment cases compared with 66 RA controls (46 versus 18%, p = 0.002). HLA-DR3 positive patients were at greater risk during treatment with D-penicillamine (RR 10.1, p = 0.001) than gold treated cases (RR 1.7, p = 0.365). The associations between HLA-DR3 and nephrotic syndrome (RR = 6.3, p = 0.004) and early onset proteinuria (RR = 5.4, p less than 0.001) were stronger compared with uncomplicated proteinuria (RR = 3.1, p = 0.017) and late-onset proteinuria (RR = 1.6, p = 0.459), respectively. It appears that genetic factors in RA influence the development, the degree and the time of onset of drug induced proteinuria.