OBJECTIVE: Summarize the current knowledge about oxidative stress-related organ dysfunction in inflammatory and septic conditions, and its potential prevention and treatment by antioxidants in critically ill patients, focusing on naturally occurring antioxidants and clinical trials. STUDY SELECTION: PubMed, MEDLINE, and personal database search. SYNTHESIS: Plasma concentrations of antioxidant micronutrients are depressed during critical illness and especially during sepsis. The causes of these low levels include losses with biological fluids, low intakes, dilution by resuscitation fluids, as well as systemic inflammatory response syndrome-mediated redistribution of micronutrients from plasma to tissues. Numerous clinical trials have been conducted, many of which have shown beneficial effects of supplementation. Interestingly, among the candidates, glutamine, glutathione, and selenium are linked with the potent glutathione peroxidase enzyme family at some stage of their synthesis and metabolism. CONCLUSIONS: Three antioxidant nutrients have demonstrated clinical benefits and reached level A evidence: a) selenium improves clinical outcome (infections, organ failure); b) glutamine reduces infectious complication in large-sized trials; and c) the association of eicosapentaenoic acid and micronutrients has significant anti-inflammatory effects. Other antioxidants are still on the clinical benchmark level, awaiting well-designed clinical trials.