The effect of cyclosporin A was tested in a heterotopic cardiac xenograft model, in which hamster hearts were implanted into LEW rats. Despite the presence of low titers of rat anti-hamster lymphocytotoxic antibodies immediate rejection of the hamster hearts did not occur, suggesting that this model represented a xenogeneic barrier of moderate strength, compatible with the close relationship of the two species. Cyclosporin A, in doses approaching toxic levels of 35 or 50 mg/kg/day for 14 days, prolonged function of the cardiac xenografts for median survival times of 21 and 11 days, respectively, in contrast to the median survival of 2 days in untreated recipients. The lymphocytotoxic antibody response of the LEW rats to the cardiac xenograft was suppressed, even in doses that did not prolong graft survival. Only the dose of 50 mg/kg/day produced any significant alteration in the histological features of rejection in the cardiac xenografts. Although cyclosporin A markedly prolonged survival of cardiac xenografts between these two closely related species, the requirement of virtually toxic levels of the drug for an effect do not suggest that this drug will be of value in transplantation of vascularized organ xenografts.