Rationale: Both insulin-like growth factor-1 (IGF-1) and bacterial clearance by Kupffer cells are significantly reduced in severe sepsis. Kupffer cell apoptosis is triggered by TNF- and activation of the PI-3 kinase pathway prevents TNF-induced Kupffer cell death. Objectives: We evaluated if the marked decline in IGF-1 is related to bacterial clearance in sepsis. Methods: Sepsis was induced in C57BL/6 mice by intratracheal inoculation with P. aeruginosa (strain PA103). Some mice received IGF-1 24 mg/kg either prior to infection or 12 hours after infection. In vitro studies were performed using the clonal Kupffer cell line KC13-2. Measurements and Main Results: Sepsis resulted in decreased levels of IGF-1. In vitro studies with KC13-2 cells demonstrated that IGF-1 protected Kupffer cells against TNF-induced apoptosis by activating the PI-3 kinase pathway and stabilizing the inhibitor of apoptosis protein, XIAP. In the animal model, pre-treatment with IGF-1 decreased hepatic TNF- and IL-6, improved hepatic bacterial clearance as demonstrated by real-time PCR with primers specific for P. aeruginosa and improved survival in severe sepsis. Moreover, we rescued mice from severe sepsis by IGF-1 treatment 12 hours after infection. Conclusions: These studies show that the decline in IGF-1 levels in sepsis is related to bacterial clearance and that replacement of IGF-1 in a murine model of sepsis improves overall survival.