This report describes the fate of orthotopic liver allografts performed in 22 donor/recipient strain combinations. Of these, 2 were major histocompatibility complex (MHC)-congenic, 18 were fully allogeneic, and 2 were non-RT1 incompatible combinations considered to differ only in minor transplantation antigens. The fate of fully allogeneic liver grafts was strictly dependent on the donor/recipient strain combination, and survival times fell into three nonoverlapping groups corresponding to acute rejection (8-21 days), delayed rejection (28-63 days), and prolonged survival (greater than 100 days). Serial levels of recipient serum enzymes also fell into groups corresponding to the fate of the graft. In 7 fully allogeneic donor/recipient combinations, liver grafts showed very prolonged survival. In five combinations they were rejected almost as quickly as kidney or heart grafts. In the two MHC congenic combinations, liver grafts survived for prolonged periods. In the non-RT1-incompatible combinations, unexpectedly, PVG livers were rejected by AUG recipients. MHC-incompatible liver grafts of a given strain survived for long periods or were rejected (in acute or delayed fashion) depending on the recipient strain. This behavior is unique to liver amongst commonly transplanted vascularized organs, and the fate of the graft clearly indicates strain-dependent levels of recipient responsiveness to defined transplantation antigens. Independent evidence supporting this conclusion is discussed. Apparently anomalous results of liver grafting in certain strain combinations are briefly considered.