The elimination of endotoxin from the blood was studied in rats with D-galactosamine-induced liver failure and in normal controls after intravenous injection of various doses of endotoxin. Endotoxin was found to localize in liver tissue by immunohistochemical staining with factor C, which is derived from amebocyte lysate of the horseshoe crab and which reacts specifically with endotoxin. Before injection, the blood endotoxin concentrations were normal both in control rats and in rats with liver failure. The blood concentrations of endotoxin were significantly higher after intravenous injection of endotoxin in the Dgalactosamine-induced liver failure group (p < 0.05) and decreased much more slowly (p < 0.05). Endotoxin concentrations were also significantly higher after in uitro incubation with plasma from rats with liver failure (p < 0.05). After intravenous injection of endotoxin (1 mg/kg), endothelial and Kupffer cells in the liver sinusoids were positively stained for endotoxin in the control group, but not stained or faintly stained in the liver failure group. Endotoxemia in liver failure thus results from reduced inactivation of endotoxin in plasma and from impaired hepatic clearance. (HEPATOLOGY 1994;19:1251-1256.) Endotoxemia has been reported to be more likely to occur in the presence of severe liver diseases such as acute hepatitis, cirrhosis and liver failure ( 1). Reduction in hepatic reticuloendothelial function and shunting between the portal and systemic circulation are the proposed mechanisms (2, 3 ) . Endotoxin absorbed through the intestine is taken into Kupffer cells in normal liver without being released into the peripheral blood (2, 3). I n the presence of liver injury, however, endotoxin can pass through the impaired reticuloendothelial system or be released into the blood through shunted portal-systemic circulation (2, 3 ) . We have demonstrated clinically and experimentally that the ability of plasma to inactivate endotoxin is reduced in the