The hepatotrophic effect of portal blood was studied in rats with portal branch ligation (PBL) simultaneously subjected to mesocaval shunt or total hepatic arterialization. A direct supply of the nonligated liver lobes with pancreatic effluent did not improve DNA synthesis or mitotic response compared to arterialized rats, in which the portal-borne hepatotrophic factors reached the same lobes after systemic recirculation. A comparison with shunted but Sham-PBL rats showed that restorative capacity of the liver was not seriously impaired. In rats with PBL alone the lobes with portal occlusion showed extensive necrosis. In contrast, in PBL + shunt rats necrosis was significantly inhibited, indicating a hepatoprotective role of portal blood during hepatic arterial recirculation. Thus, the study suggests that quality of hepatic blood supply is of vital importance in maintenance of hepatocellular integrity. Hemodynamical factors seem to be of importance, but more in a sense of increased or decreased accessibility of humoral hepatotrophic factors in the blood.