It has been reported that oral interleukin (IL)-6, without deleterious systemic side effects, prevents bacteremia and gut epithelial apoptosis after hemorrhagic shock (HS) in rodents. The goal of this study was to explore potential benefit of oral or enteral IL-6 on the gut and, consequently, on survival in a long-term outcome model of HS in rats. In Study A, 20 rats (control and IL-6, n = 10 per group) were anesthetized by spontaneous breathing of halothane and N2O. The left femoral vein and artery were cannulated. HS was initiated with withdrawal of 3 mL of blood per 100 g body weight over 15 min, and mean arterial pressure was maintained at 40 to 50 mmHg for another 75 min (total HS 90 min) by blood withdrawal or infusion of Ringer's solution. At HS 90 min, resuscitation included reinfusion of shed blood and additional Ringer's solution to restore normotension for 30 min. After awakening at resuscitation time 30 min, the rats received either 300 units IL-6 or the same volume of vehicle (controls) injected into the stomach via a feeding cannula. In Study B, 20 rats (control and IL-6, n = 10 per group), fasted overnight, were prepared and treated as in Study A, except that HS was initiated with withdrawal of 2 mL blood per 100 g over 10 min, and mean arterial pressure was maintained at 35-40 mmHg. IL-6 rats received 3,000 units IL-6 in 5 mL of normal saline injected directly into the ileum lumen 20 min after induction of shock and again at resuscitation time 60 min. Control rats received normal saline alone. In both studies, survival was observed to 72 h. In Study A, 7 of 10 rats in the control group and 5 of 10 in the IL-6 group survived to 72 h (NS). Macroscopic assessment of gut injury was not different between the two groups. In Study B, 6 of 10 rats survived to 72 h in each group. Frequency of bacteria growth in liver tissue of 72 h survivors was not different between the two groups. IL-6, administered into the stomach or directly injected into the small intestine lumen, did not protect the gut from ischemic injury, nor did it improve survival following severe HS in rats.