Gut-origin sepsis is a serious medical complication of military injuries following hemorrhage. Splanchnic ischemia induces intestinal necrosis leading to systemic bacteremia. Rat and mouse models of hemorrhagic shock were used to investigate bacterial translocation from the gut. Orally administered ameliorative treatments using the cytokine interleukin-6 (IL-6) were able to reduce or eliminate sepsis following hemorrhage. To mimic battlefield wounds and hemorrhage, anesthetized mice were bled from the femoral artery, held at a mean arterial blood pressure of 35 mm Hg for 1 hour, and then resuscitated with shed blood and 2-fold volume lactated Ringer's solution. Anesthetized rats were bled from the carotid artery at a rate of 15 ml/kg at 1 ml/minute. Bacteriological cultures of livers and mesenteric lymph nodes from hemorrhaged animals given recombinant IL-6 had significantly fewer colonies per gram of tissue than saline-fed controls. 125I-labeled IL-6 remained in the gut for up to 6 hours giving regional protection, whereas labeled interleukin-2 was disseminated throughout the body in the same time. In vivo and vitro studies of IL-6 showed that long incubations with high doses of trypsin, chymotrypsin, or intestinal contents were necessary to inactivate the bioactivity of this cytokine. Electron microscopy showed that epithelial cells from hemorrhaged mice fed saline had sparse or missing villi and vacuolated cytoplasm. Epithelial cells from control mice or mice hemorrhaged and fed cytokine appeared completely normal. Oral administration of IL-6 on the battlefield may be an important treatment for the prevention of sepsis following hemorrhage.