The potential use of peripheral nerve allografts would significantly improve the reconstructive potential for patients with major peripheral nerve deficits. This study evaluated the response of the nerve allograft recipient treated with varying dosages of cyclosporin A (CsA) to determine the minimal effective dosage necessary to prevent nerve graft rejection. Lewis rats (RT11) were the recipients of syngeneic nerve grafts from identical Lewis donors or allogeneic nerve grafts from ACI (RT1a) donors. Nerve grafts were inlaid next to the intact sciatic nerve of the recipient. The immunologic responsiveness of the recipient animal’s lymphocytes to a donor-specific antigenic challenge was assessed by the mixed lymphocyte reaction (MLR). In addition, nerve grafts were evaluated histologically. Animals were monitored for cyclosporin A toxicity. It was found that cyclosporin A (5 mg/kg per day) was effective in rendering the recipient animals unresponsive by mixed lymphocyte reaction at 10, 20, and 40 days after engraftment. This dosage was similarly effective in preventing histologic changes characteristic of nerve allograft rejection. This dosage regimen was nontoxic to the animals. Our study ascertained a minimal nontoxic dosage of cyclosporin A that effectively prevented nerve allograft rejection across a major histocompatibility disparity in rats.