The effects of ischemia on the regenerative capacity of the liver after major tissue loss remain unclear. Interleukin-6 (IL-6) has been shown to confer protection in models of normothermic ischemia and reperfusion injury and to initiate hepatocyte proliferation after major hepatectomy. Therefore, we investigated the effects of ischemia on the regenerative capacity of the liver and evaluated the role of IL-6 in reducing reperfusion injury and enhancing hepatic proliferation in models combining ischemia and major hepatectomy. Rats subjected to 70% hepatectomy and 30 minutes of hepatic ischemia showed significantly reduced regenerative capacity (mitotic index, proliferating cell nuclear antigen, and regenerated liver weight) when compared with animals subjected to hepatectomy alone. Pretreatment of animals subjected to hepatectomy and ischemia with recombinant interleukin-6 (rIL-6) completely restored each parameter of regeneration to levels comparable with those of animals subjected to hepatectomy only. Similar results were obtained in IL-6 deficient (IL-6−/−) mice. IL-6−/− mice exposed to ischemia and hepatectomy showed impaired hepatic regeneration when compared with wild-type mice subjected to the same experimental conditions. The use of rIL-6 completely corrected each parameter of regeneration showing the specificity of IL-6 in this type of injury. The impact of IL-6 on animal survival was studied in a model combining 45 minutes of ischemia and 68% hepatectomy. Five of 7 (71%) animals pretreated with rIL-6 survived permanently, whereas all control animals died within 3 days of surgery (P = .02, Fisher's exact test). In conclusion, the study shows that ischemia dramatically impairs the regenerative capacity of the liver. IL-6 appears to be a key protective molecule in reducing injury and promoting regeneration following combined ischemia and major tissue loss.