Hematologic toxicity occurred when trimethoprim-sulfamethoxazole was given for prolonged periods to renal allograft subjects also treated with azathioprine. In six such patients, the incidences and duration of neutropenia and thrombocytopenia were greater than in 25 similar allograft recipients treated with azathioprine alone. In bone marrow culture, the antifolate action of trimethoprim-sulfamethoxazole enhanced the marrow-suppressive effect of 6-mercaptopurine, the active moiety cleaved from azathioprine. These studies show that in renal allograft recipients treated with azathioprine, the prolonged use of trimethoprim-sulfamethoxazole may result in life-threatening hematotoxicity.