Nonarterialized orthotopic liver transplantation with no immunosuppression was performed in 13 mouse‐strain combinations. Two strain combinations with major histocompatibility complex class I and class II and minor histocompatibility complex disparity had 20% and 33% survival of more than 100 days, but the other 11 combinations, including four that were fully allogeneic and all with only class I, class II or minor disparities, yielded 45% to 100% survival of more than 100 days. Long‐living recipients permanently accepted donor‐strain heterotopic hearts transplanted on the same day or donor‐strain skin 3 mo after liver transplantation, in spite of detectable antidonor in vitro activity with mixed lymphocyte reaction and cellmediated lymphocytotoxicity testing (split tolerance). In further donor‐specific experiments, liver grafts were not rejected by presensitized major histocompatibility complex class I‐disparate recipients and they protected donor‐strain skin grafts from second set (or any) rejection. Less frequently, liver transplantation rescued rejecting skin grafts placed 1 wk earlier in major histocompatibility complex class I, class II and minor histocompatibility complex, class II or minor histocompatibility complex‐disparate strain combinations. Donor‐derived leukocyte migration to the central lymphoid organs occurred within 1 to 2 hr after liver transplantation in all animals examined, persisted in the surviving animals until they were killed (>375 days), and was demonstrated with double‐immunolabeling to be multilineage. The relation of these findings to so‐called hepatic tolerogenicity and to tolerance in general is discussed. (HEPATOLOGY 1994;19:916–924.)