Oxidative stress due to an overwhelming release of reactive nitrogen/ oxygen species (R(N)OS) is held largely responsible for sepsis-induced organ failure and mortality. Excessive R(N)OS production is neutralized by endogenous antioxidants (reduced glutathione (GSH), enzymes such as GSH peroxidase, and antioxidant vitamins) but this antioxidant potential becomes dramatically reduced in sepsis. Exogenous antioxidant supplementation may aid to restore antioxidant capacity. The literature on antioxidant therapy in sepsis is reviewed. Particular attention is given to clinical application. Selected articles focus on N-acetylcysteine (NAC), selenium, the antioxidant vitamins C and E, and NO synthase inhibition. In general, these substances display potent antioxidant activity in association with improved haemodynamic and organ function in animal experiments and in small clinical trials. Differences in dosing, time to start, and duration of treatment (NAC and selenium), the impossibility to judge its intrinsic effect because of concomitant treatment with other anti-inflammatory or immune-enhancing agents (vitamins C and E)), and even worsening of cardiac function and outcome (NAC and non-selective NO synthase inhibition) question the potential role of these agents in sepsis treatment. Copyright © 2008, Nederlandse Vereniging voor Intensive Care. All Rights Reserved.