Objective: To assess whether dietary supplementation with the antioxidant vitamins A, C, and E enhances parameters of oxidative stress and influences the course of critically ill patients. Design: Prospective, randomized, double-blinded, placebo-controlled study. Setting: Department of medicosurgical intensive care of an academic hospital. Patients: Fifty-one patients expected to require at least 7 days of enteral feeding. Thirty-seven of these patients (age, 57 +/- 7 yrs; Simplified Acute Physiology Score II, 33 +/- 6 points) completed the study. Interventions: Twenty patients were randomized to receive the formula supplemented with vitamins A (67 mug/dL), C (13.3 mg/dL), and E (4.94 mg/dL), and 17 patients received an isocaloric and isonitrogenous control solution. Measurements and Main Results: Plasma levels of antioxidant vitamins, lipid peroxidation (estimated by the malonyldialdehyde assay), and low-density lipoprotein (LDL), and erythrocyte resistance to experimental oxidative stress were determined an samples drawn two consecutive days before the initiation of feeding and at the end of the 7-day period. Clinical outcome measures included documented infection and intensive care unit and 28-day survival. Administration of the supplemented solution increased significantly the concentration of plasma beta -carotene (from 0.2 a 0.0 mug/mL to 0.6 +/- 0.1 mug/mL; p < 0.01) and plasma and LDL-bound <alpha>-tocopherol (from 6.0 +/- 0.4 mug/mL and 2.9 +/- 0.9 mug/mL to 9.7 +/- 0.5 mug/mL and 4.3 +/- 1.2 mug/mL, respectively; p < 0.05), and improved LDL resistance to oxidative stress by 21 +/- 4% (p < 0.05). No such change was observed in the control group. There was no significant difference in clinical outcome between the two groups. Conclusions: Supplemental antioxidant vitamins added to enteral feeding solutions are well absorbed. Dietary supplementation with vitamins A, C, and E is associated with an improvement in antioxidant defenses, as assessed by ex vivo tests.