To replace the autologous graft as a clinical treatment of peripheral nerve injuries we developed an optimized acellular (OA) nerve graft that retains the extracellular structure of peripheral nerve tissue via an improved chemical decellularization treatment. The process removes cellular membranes from tissue, thus eliminating the antigens responsible for allograft rejection. In the present study, the immunogenicity and regenerative capacity of the OA grafts were tested. Histological examination of the levels of CD(8+) cells and macrophages that infiltrated the OA grafts suggested that the decellularization process averted cell-mediated rejection of the grafts. In a subsequent experiment, regeneration in OA grafts was compared with that in isografts (comparable to the clinical autograft) and two published acellular graft models. After 84 days, the axon density at the midpoints of OA grafts was statistically indistinguishable from that in isografts, 910% higher than in the thermally decellularized model described by Gulati (J. Neurosurg. 68, 117, 1988), and 401% higher than in the chemically decellularized model described by Sondell et al. (Brain Res. 795, 44, 1998). In summary, the results imply that OA grafts are immunologically tolerated and that the removal of cellular material and preservation of the matrix are beneficial for promoting regeneration through an acellular nerve graft.