Cyclosporine was evaluated for its ability to delay or prevent accelerated rejection in a model of the second-set immune response. Lewis rats sensitized by LBN skin grafts or subcutaneous heart fragments experienced accelerated rejection of heterotopic, vascularized LBN hearts with a mean survival time (MST) of approximately 5 days versus MST of 9.5 days for primary grafts. A short course of cyclosporine (10 mg/kg/day for 10 days) significantly prolonged graft survival in presensitized hosts to approximately 12 days (P less than 0.01) as compared with the nontreated controls. Adjunctive splenectomy failed to further extend graft survival; MSTs were 12.0 and 5.7 days with and without cyclosporine, respectively. A comparable abrogation of second-set rejection was also achieved with a short course of antithymocyte serum (MST of 10.6 days). Rejection promptly ensued in all of the above groups shortly after cessation of immunosuppression. In contrast, a maintenance regimen of cyclosporine, given in a tapering dose, markedly extended graft survival to from 77 to 100+ days. Again, however, rejection eventually occurred following withdrawal of the cyclosporine. These data suggest that cyclosporine can indeed effectively prolong allograft survival in presensitized hosts.