Acute hepatic necrosis was induced by a single i.v. injection of lipopolysaccharide (LPS) into C57BL/6 mice following immunization with syngeneic liver protein and adjuvant. Sixty percent of the mice died of massive hepatocyte necrosis within 48 hours of LPS injection. The serum lactate dehydrogenase and aspartate aminotransferase levels were markedly elevated. The fatal and hepatotoxic action of LPS was prevented by pretreatment with FUT-175 (1.6 mg/kg), a synthetic protease-inhibitor. The inhibitory effects of FUT-175 was not demonstrated when the agent was given to the mice 2 h after the administration of LPS. These results seem to indicate that the hepatotoxic effects of LPS are mediated by endogenous host mechanisms in which proteases play an important role.