Peripheral nerve allografting has been the subject of many experimental and clinical studies. As yet, however, no successful method has been established. One reason is the lack of detailed studies on the immune response under different conditions. We examined both the cellular and humoral immune responses in fresh sciatic nerve allografts in inbred mice, using a mixed lymphocyte culture reaction and a lymphocyte-mediated cytotoxicity to examine cellular immunity and a complement-dependent cytotoxicity test to examine humoral immunity. Enhanced MLC activity against donor allogenic major histocompatibility complex antigens was demonstrated, and specific cytotoxic T cell activity and the production of specific antigens in serum also were observed. Thus peripheral nerve tissue exhibited potent immunogenicity.We used cyclosporine, an immunosuppressive agent, to suppress the immune response and obtain favorable nerve regeneration. We performed immunologic and histologic studies to establish a causal relationship. Administration of 20 mg of CsA suppressed both the cellular and humoral immune response to levels comparable to those seen in isografting. Histologic examination disclosed favorable regeneration of axons, also comparable to that seen in isografts.