Increased small bowel epithelial cell apoptosis and decreased cell proliferation leads to impairment of gut mucosal integrity and function after thermal injury. Impairment of gut integrity is associated with increased bacterial translocation and incidence of sepsis. The purpose of this study was to determine whether IGF-I/BP-3 can improve small bowel homeostasis after injury and by which cellular mechanisms these changes occur. To identify changes in apoptosis related genes postburn and the effect of bile acid on small bowel epithelial cell apoptosis postburn. Rats sustained a thermal injury and received saline or the IGF-I/BP-3 complex. Serum and small intestine were taken at 1, 2, 5 and 7 days after injury and serum inflammatory cytokines and mucosal apoptosis, proliferation, villous morphology, apoptotic and proliferative mediators were measured. Apoptosis related gene expression and the bile acid pool were determined in separate experiments up to 6 h postburn. Gut epithelial cell apoptosis as well as apoptosis related genes were increased after the thermal injury, while bile acid secretion was significantly decreased (P < 0.05). IGF-I/BP-3 significantly improved villous height and cells per villous by decreasing small bowel epithelial cell apoptosis and increasing proliferation (P < 0.05). Decreased apoptosis was associated with decreased Fas, Fas-L and TNF when compared with saline (P < 0.05). A severe thermal injury caused an up-regulation of apoptosis and apoptosis related genes and down regulation of bile acid secretion. IGF-I/BP-3 decreases small bowel epithelial cell apoptosis through down regulation of the Fas pathway, which improves gut mucosal integrity after a severe thermal injury.