Oxidative stress defines an imbalance in production of oxidizing chemical species and their effective removal by protective antioxidants and scavenger enzymes. Evidence of massive oxidative stress is well established in adult critical illnesses characterized by tissue ischemia–reperfusion injury and by an intense systemic inflammatory response such as during sepsis and acute respiratory distress syndrome. Oxidative stress could exacerbate organ injury and thus overall clinical outcome. We searched MEDLINE databases (January 1966 to June 2005). For interventional studies, we accepted only randomized trials. Several small clinical trials have been performed in order to reduce oxidative stress by supplementation of antioxidants alone or in combination with standard therapies. These studies have reported controversial results. Newer large multicenter trials with antioxidant supplementation should be performed, considering administration at an early stage of illness and a wider population of critically ill patients.