Acute liver failure is associated with high mortality. Whether support with transplanted hepatocytes improves the outcome is not established. We studied the potential beneficial effects of intrasplenic transplantation of hepatocytes in conjunction with islets of Langerhans on 90% hepatectomy-induced acute liver failure in rats. We found that all control rats died within 48 hr following 90% hepatectomy. In contrast, the mortality decreased significantly in rats transplanted with 10(7) hepatocytes into the spleen parenchyma at 1-3 days prior to 90% subtotal hepatectomy, whereas no significant reduction in mortality was seen in rats transplanted with hepatocytes immediately after the operation. However, cotransplantation of hepatocytes and 400 isolated pancreatic islets into the spleen reduced mortality when performed immediately after the 90% hepatectomy. Therefore, hepatocyte transplantation reduces mortality after 90% hepatectomy only if performed prior to the hepatectomy. However, transplantation of hepatocytes in conjunction with pancreatic islets reduces mortality when performed at the same time as 90% hepatectomy. Hence, the combined transplantation of hepatocytes and islets might offer support after liver failure.