Recent studies have shown that monoclonal antibodies (MAbs) to cell surface molecules (ICAM-1, LFA-1) prolonged various allograft survivals. The purpose of this study was to evaluate the immunosuppressive effect of MAbs to ICAM-1 and LFA-1 in the mouse peripheral nerve allograft. M&M C3H recipient mice (n = 27) were transplanted with 15-mm segments of sciatic nerve from Balb/c (allograft) and C3H (isograft) donor mice. These animals were divided into three groups: Group I, isograft; Group II, allograft without MAb therapy; Group III, allograft with anti-ICAM-1 and anti-LFA-1 MAbs (6 mg/kg, i.p., q.o.d., 2 weeks). MAb in recipient circulation was assessed with flow cytometry at 1 and 3 weeks after final treatment. Nerve regeneration was histologically evaluated at 8 weeks. Skin graft at 9 weeks and CTL assay at 12 weeks assessed recipient immune responsiveness. Although MAbs in the circulation were undetectable 3 weeks after final treatment, MAb-treated recipients continued to accept nerve allografts for 8 weeks, and directed excellent nerve regeneration equal to the isografts. The untreated allograft showed a complete disruption of fascicular architecture with poor nerve regeneration and with prominent cellular infiltration. The mean survival time of donor skin grafts was prolonged in the MAb-treated animals (17.5 vs. 11.5, p < 0.01), but MAb therapy had no effect on third-party skin graft (12.5 vs. 12.8, NS). CTL activity in the MAb-treated recipients was specifically suppressed against the nerve-donor target cells (%lysis: 33.3 ± 3.4 vs. 79.0 ± 10.0, p < .01), but not against third-party target cells (58.7 ± 4.9 vs. 45.0 ± 11.9, NS). A short course of MAb therapy to ICAM-1 and LFA-1 induced long-term immunosuppression and permitted excellent nerve regeneration across nerve allografts. The suppressive effect demonstrated was specific for nerve-donor antigen and other immune function was not impaired. MAb therapy to ICAM-1 and LFA-1 represents a new area in the management of peripheral nerve allografting with the potential for future clinical applications.