In the management of heart transplant patients, treatment of acute rejection, as diagnosed by means of endomyocardial biopsy, is critical. Standard antirejection agents include corticosteroids, antithymocyte globulin, and orthoclone. In addition to these drugs, we used increased dosages of cyclosporine to treat 27 episodes of moderate allograft rejection in 24 patients. To qualify for inclusion in this study, patients could not show signs of cyclosporine toxicity despite normal (200 to 300 ng/ml) or high cyclosporine levels and clinical signs of rejection. Therapy consisted of increased oral dosages of up to 14 mg/kg/day of cyclosporine in addition to 1 to 3 mg/kg/day of intravenous cyclosporine. In all 24 patients high levels of cyclosporine were maintained until signs of toxicity appeared, at which point the dosage was adjusted. If endomyocardial biopsy indicated improvement, the dosage was readjusted to maintain cyclosporine levels between 200 and 300 ng/ml. Treatment was successful in 22 cases (81.5%). We compared this group of patients with a not randomly selected but time-overlapping group of 32 patients, who received a steroid pulse for moderate allograft rejection. The incidence of infectious episodes was significantly lower in the cyclosporine-treated patients than in patients given a steroid pulse. There were no signs of permanent kidney or liver damage during or after treatment with increased dosages of cyclosporine. Therefore we conclude that increased dosages of cyclosporine are safe and effective in treating moderate allograft rejection.