The immunosuppressive effects of cyclosporin A were tested in a DA (RT-1 a ) to Lewis (RT-1 1 ) rat renal allograft model, which represents a very strong histocompatibility barrier. Dose-response studies established that oral doses of 5 mg/kg/day or higher gave complete suppression of rejection, while oral doses of 2 mg/kg/day or lower were without effect. Intravenous administration of the drug approximately doubled its potency. Time studies showed that the period of administration was also critical, with a 7− or 14-day treatment course with 5 mg/kg/day orally giving prolonged graft survival, while a 4-day course was without effect. Large doses (up to 25 mg/kg/day orally) from day 4 after transplantation did not prolong graft survival, suggesting that cyclosporin A has no effect on an established rejection response. It was found that the lymphocytotoxin response to the graft was markedly suppressed by doses of cyclosporin A which maintained normal graft function, while lower doses had little or no effect on the lymphocytotoxin response. A cell-mediated immunity assay showed a substantial response, but one that was lower in amplitude from that of control animals. Histological study of 7th day allograft biopsies demonstrated essentially normal kidneys, except for a mild mononuclear cell infiltrate, at higher doses of cyclosporin. Lower doses of cyclosporin gave a picture of rejection no different from that seen in untreated controls. The LD 50 of cyclosporin was found to lie between 50 and 100 mg/kg/day orally. Even the higher of these doses did not cause nephrotoxicity as determined biochemically and histologically.