Endotoxin [etox] of enteric origin may contribute to acute and chronic liver injury by other agents. Etox tolerance modifies biochemical and histological evidence of CCl4 hepatotoxicity. The antibiotic polymyxin B (PB) has unique anti-etox properties not shared by gentamicin sulfate, an antibiotic with a similar anti-bacterial spectrum. In groups of rats pre-treated with PB, gentamicin or diluent, the LD100 of an oral dose of CCl4 was reduced by PB to an LD50, but the gentamicin pre-treatment was without effect. When a sublethal dose of CCl4 was administered, the SGOT [serum glutamic oxaloacetic transaminase] and SGPT [serum glutamic pyruvic transaminase] values were significantly lower in the PB group of rats. This biochemical protection was mirrored in the striking lack of histological liver necrosis in these animals, protection not shared by the gentamicin group or controls. The incidence of endotoxemia 24 h after CCl4 as detected by lead acetate enhancement was reduced by PB pre-treatment. Etox from the gut may be major contributors to the extent of liver injury induced by an unrelated toxin.