Although some allografts bearing major and minor transplantation antigens can survive after the cessation of immunosuppression with cyclosporin-A (Cy-A), nerve allografts do not. In an attempt to induce immunological unresponsiveness to nerve allografts, we used grafts containing only minor transplantation antigens and varied the duration of Cy-A therapy from 2 to 12 weeks. Our results demonstrated that nerve allografts survived in rats during Cy-A therapy, but when the drug administration ceased, the allografts were rejected. Other factors besides the degree of histoincompatibility and duration of Cy-A treatment must be involved in determining whether or not unresponsiveness develops to allografts after Cy-A withdrawal. We conclude that nerve allograft immunosuppression generated by Cy-A requires regular administration of the drug.