Splenocytes sensitized in vitro to the H-2 allotype of a skin allograft have been shown to cause accelerated rejection of the skin allograft after adoptive transfer of the splenocytes. Treatment of the host with splenectomy or sublethal radiation did not alter the accelerated rejection. In the present study, cyclosporine (CsA) given subcutaneously to mice bearing 1 day old skin grafts prevented the rejection of the graft despite the adoptive transfer of sensitized cells. If the CsA was given for 14 days at 50 mg/kg every other day, the grafts were rejected an average of 6 days after the cessation of CsA. If the CsA was given for 20 days 50 mg/kg every other day, the grafts were not rejected even after cessation of CsA. When no sensitized cells were given, the same pattern resulted; that is, when a 14 day course of CsA was given the grafts were rejected after cessation of the CsA but when a 20-d course was given, the grafts were not rejected even after the CsA was stopped. If splenocytes were sensitized in the presence of interleukin-2 (IL-2), they caused rejection of the skin allografts in animals even on treatment with CsA. We concluded that CsA can prevent skin allograft rejections in the murine system. Moreover, the dose of CsA was critical, in that a longer course of CsA was necessary for tolerance. CsA further prevented the accelerated rejection of skin allografts by adoptive transfer of specifically sensitized splenocytes. Donor irradiation did not alter the effect of the CsA or of the adoptively transferred cells. CsA could not prevent the rejection of skin allografts when the adoptively transferred cells were sensitized to antigen in the presence of IL-2.