An autoimmune syndrome occurs in cyclosporine-treated, lethally irradiated, and marrow-reconstituted rats after cyclosporine is discontinued. This syndrome, referred to as cyclosporine-induced autoimmunity, requires the presence of a thymus. In this report, we demonstrate that the disease will occur in animals transplanted with thymus tissue from an allogeneic donor, incompatible with the recipient at the major histocompatibility complex. T cells generated from these allogeneic thymic chimeras respond in vitro to thymic donor antigens, suggesting that cyclosporine inhibits self-tolerance induction in the thymus. Because disease is more frequent when the tolerizing antigens expressed in the thymus differ from those expressed in the periphery, the possibility that cyclosporine may mediate its effect via the downregulation of self-antigen presented in the thymus is discussed.