Current information suggests that oxidative damage plays a key role in septic shock induced by endotoxin. This raises the possibility that dietary antioxidant vitamins could protect against endotoxin damage. In this study, the effects of endotoxin administration on protein and lipid oxidative damage and endogenous antioxidants were studied in the liver of guinea pigs previously supplemented with marginal or optimum levels of dietary vitamin C, vitamin E or both. Vitamins C and E inhibited in vitro lipid peroxidation in endotoxin-treated animals. Endotoxin significantly increased oxidative damage to liver proteins in animals receiving low doses of both vitamins, a result described here for the first time. This increase was totally prevented in guinea pigs supplemented with vitamin C alone or in combination with vitamin E, a treatment which strongly increased liver ascorbate. Vitamin C caused small significant increases in superoxide dismutase and glutathione, increased uric acid, and synergically increased alpha-tocopherol levels in vitamin E-supplemented animals treated with endotoxin. The results show that dietary vitamin C protects against endotoxin-induced oxidative damage to proteins in the guinea pig liver. This seems mainly due to a direct protective effect of the increased hepatic ascorbate levels present in vitamin C-supplemented animals.