Sepsis remains a leading cause of death in the surgical intensive care unit (SICU) patient following major surgery or trauma. Recent work has demonstrated that oxygen-free radicals (OFR) generated during sepsis contribute to the pathogenesis of this syndrome. The purpose of this study was to evaluate the effect of various new free radical scavengers on survival in sepsis. A total of 85 male Sprague-Dawley rats were placed into one of the following treatment groups. METHODS cecal ligation and puncture (CLP); PRE-AT: pretreatment with alpha-tocopherol (AT) 10 mg/100 gm SC x 3 days, and 5 mg/100 gm IV prior to CLP; AT: 20 mg/100 gm at time of CLP and 4 hours following CLP; U74006F: (21-aminosteroid which inhibits lipid peroxidation) 3 mg/kg IV at the time of and 4 hours following CLP; U78517F: (alpha-tocopherol analogue) 3 mg/kg at the time of and 4 hours following CLP. Survival was determined at various time points up to 72 hours. Pretreatment with AT resulted in improved survival, whereas the novel OFR scavengers U78517F and U74006F significantly improved survival and were efficacious without pretreatment. It was concluded that OFR scavengers can improve survival in sepsis.