The relationship between liver regeneration and the induction of the immune response is uncertain. We hypothesize that the altered environment of the regenerating liver allograft increases the immune response to the allograft. In DA (RT1a) to LEW (RT1I) rats, hepatectomized, small-for-size and whole, normal-for-size liver transplants were performed. Naive and 70% hepatectomized LEW served as controls. Animals were assessed for survival, mass restoration, and host alloresponses. Although 30% partial allografts regenerated well to achieve a volume nearly equal to that of recipient's native liver in 7 days, survival was significantly shorter than that of the recipients of whole grafts (8.8 +/- 0.4 vs 10.3 +/- 1.2 days, n = 6, P < 0.02). When compared on Day 4 after transplantation, histologic examination revealed a more vigorous cellular infiltration in the sinusoidal area in the partial liver transplant group. Phenotypic analysis of thymocytes showed a predominance of more mature phenotypes in the partial group, including more prominent decrease in the frequency of CD4, CD8-double-positive cells and increase in that of alpha beta TCRhigh cells. Proliferative activity of thymocytes in response to Con A was higher in the partial group than in the whole group. MLR of splenocytes against donor-type antigens was higher in the partial group, whereas reactivity against third party was the same as in other groups. These data suggest that host cellular responses to the allograft are enhanced in the regenerating, small-for-size liver graft. These findings have implications in the clinical management of liver recipients with damaged or small for size livers.