Since endotoxin, lipopolysaccharides (LPS), have been implicated as a causative factor in the development of hepatic necrosis in rats exposed to hepatotoxic levels of several chemical agents, the role of LPS in the halothane–hypoxia (HH) model of hepatic damage in male Sprague–Dawley rats was investigated. When injected intravenously immediately after halothane anesthesia, a subnecrotic dose of LPS (0.5 mg/kg;Escherichia coli026:B6) was found to markedly potentiate HH-induced hepatic necrosis. Pretreatment of the animals with the antiendotoxin agent, lactulose, prior to exposure to halothane reduced the hepatic damage normally seen from HH. A possible mechanism of LPS-induced potentiation was indicated by changes in hepatic calcium levels at 24 h after treatment. Endogenous LPS may play a role in HH-induced hepatic necrosis, and the mechanism of LPS-induced potentiation may be due to an LPS-related membrane dysfunction.