Twenty-five patients with rheumatoid arthritis treated with D-penicillamine were retrospectively reviewed for signs of drug intolerance. Nine patients (36%) developed adverse drug reactions, the most common of which was proteinuria in six patients (24%). Comparative analysis of patients with and without penicillamine-induced proteinuria revealed the only significant correlate to be a previous history of gold nephropathy. Five (83%) of six patients who developed penicillamine-induced proteinuria had had gold-induced proteinuria; in contrast, only three (20%) of 19 who tolerated penicillamine had prior gold-induced proteinuria (p less than .01). HLA typing performed in five of the six patients with penicillamine nephropathy revealed DRw4 at a prevalence less than that expected for a population with rheumatoid arthritis, with DRw3 and/or B8 present in four patients. Further studies are in progress to determine whether a genetic predisposition is present. These data suggest that cautious observation is warranted in rheumatoid patients receiving D-penicillamine who have a prior history of gold nephropathy.