Repopulation of the cirrhotic liver with disease-resistant hepatocytes could offer novel therapies, as well as systems for biological studies. Establishing whether transplanted hepatocytes can engraft, survive, and proliferate in the cirrhotic liver is a critical demonstration. Dipeptidyl peptidase IV-de®cient F344 rats were used to localize transplanted hepatocytes isolated from the liver of syngeneic normal F344 rats. Cirrhosis was induced by administration of carbon tetrachloride with phenobarbitone and these drugs were withdrawn prior to cell transplantation. Cirrhotic rats showed characteristic hepatic histology, as well as signi®cant portosystemic shunting. When hepatocytes were transplanted via the spleen, cells were distributed immediately in periportal areas, ®brous septa, and regenerative nodules of the cirrhotic liver. Although some transplanted cells translocated into pulmonary capillaries, this was not deleterious. At 1 week, transplanted cells were fully integrated in the liver parenchyma, along with expression of glucose-6-phosphatase and glycogen as reporters of hepatic function. Transplanted cells proliferated in the liver of cirrhotic animals and survived inde®nitely. At 1 year, transplanted hepatocytes formed large clusters containing severalfold more cells than normal control animals, which was in agreement with increased cell turnover in the cirrhotic rat liver. The ®ndings indicate that the cirrhotic liver can be repopulated with functionally intact hepatocytes that are capable of proliferating. Liver repopulation using diseaseresistant hepatocytes will be applicable in chronic conditions, such as viral hepatitis or Wilson's disease.