The nerve allograft response between closely and distantly related inbred strains of rats was investigated. Lewis rats (RT11) and Fischer rats (RT11) have only minor histocompatibility differences, whereas Buffalo rats (RT1(b)) and ACI rats (RT1(a)) differ from Lewis rats at the major histocompatibility locus. Lewis rats served as the recipient animals; the other three strains of rats provided donor nerves. The 51Cr release cytotoxicity assay was used to assess antigen recognition. The results showed sensitization with ACI and Buffalo nerves as early as Day 8. When the donor and recipient were matched (Lewis/Fischer), sensitization occurred very late (Day 80). By contrast, with skin allografts, sensitization occurred early with all strains (Day 10), even when the animals differed only at the minor histocompatibility loci. Histological changes were similar in all three donor strains (Fischer, Buffalo, ACI). The strain of origin of the nerve could not be deduced by an unbiased examiner.