Peripheral nerve allotransplantation allows the reconstruction of injuries with long nerve gaps that are otherwise unsalvageable. In this study, the efficacy of anti-CD4 monoclonal antibody (mAb) combined with donor antigen pretreatment in prolonging the survival of short peripheral nerve allografts was investigated in a rodent model. Such an approach could potentially avoid the need for systemic immunosuppression and its concomitant morbidities. Buffalo rats received either nerve isografts or nerve allografts from Lewis rats. Untreated isograft and allograft groups were used as controls. Allograft recipients received either a single dose of RIB 5/2, a non-depleting anti-CD4 mAb, a single dose of Lewis splenocytes, or both antigen and RIB 5/2, 7 days prior to transplantation. Flow cytometric analysis verified that the T-lymphocyte population was maintained, while CD4 expression was downregulated by RIB 5/2. Histologic evaluation demonstrated better regeneration in the allograft recipients receiving both donor antigen and antibody, compared to recipients of untreated allografts or treatment with antigen or antibody alone.