Three new observations bear out the role of endogenous endotoxins in the pathogenesis of murine hepatitis caused by frog virus 3. First, the LD50 of endotoxin is 20 times lower in mice pretreated for 2.5 hr with a sublethal dose of frog virus 3 than in untreated mice. Animals inoculated with one sublethal dose of lipopolysaccharide 2.5 hr after injection of one sublethal dose of virus die, all having developed extensive hepatocellular necrosis. This hypersensitivity varies according to the intensity of virus-induced destruction of Kupffer cells, which are the intrahepatic target of the virus. Second, mortality is significantly lower and the interval between infection and death longer in axenic mice, which are largely protected from portal endotoxemia. Third, the impairment of some biologic activities of endotoxin (through treatment with polymyxin B or indomethacin, for example) protects mice against hepatic damage and death. Likewise, mice rendered tolerant to endotoxins, and C3H/HeJ mice, which are genetically resistant to endotoxins, survive challenge with frog virus 3 and are refractory with regard to hepatocytolysis . These findings suggest that, in hepatitis caused by frog virus 3, endogenous endotoxins are responsible for extensive hepatocytolysis since virus-induced damage to the hepatic reticuloendothelial system prevents their detoxification.