Oxygen-free radicals are produced during sepsis, and may contribute to cell injury and dysfunction. We studied the effect of different levels of vitamins E and C in the diet fed enterally to septic guinea pigs. Sixty-four female guinea pigs were provided with gastrostomies and allowed to recover. Intraperitoneal osmotic pumps were then implanted that provided effusion of Escherichia coli and Staphyloccus aureus for the next 7 days. Three days after pump implantations, the animals were started on one of nine diets. The diets were isocaloric and isonitrogenous, and differed only in the amounts of vitamins E and C. Three levels of each vitamin were used, based on the Recommended Daily Allowance (RDA). The feedings were continued for 2 weeks, during which time mortality was observed. The amount of vitamin C had no effect on outcome, with mortality rates of 68% (15/22) in the 1 x RDA group, 73% (16/22) in the 5 x RDA group, and 65% (13/20) in the 25 x RDA group. However, vitamin E altered outcome significantly, with mortality rates of 86% (18/21) in the 1 x RDA group, 45% (10/22) in the 3 x RDA group, and 76% (16/21) in the 9 x RDA group. Mortality in the 3 x RDA group was significantly lower than that in the 1 x RDA group and in the 9 x RDA group. We conclude that supplemental vitamin C has no effect on outcome in this model. However, survival in guinea pigs with peritonitis appears to be sensitive to the amount of vitamin E in the diet. We conjecture that low levels of vitamin E may be inadequate to protect against lipid peroxidation during sepsis.