Extreme hepatectomy or resection of more than 80% of liver mass often leads to liver failure and death and is a major limitation to therapeutic liver resection for patients with liver tumors. We sought to define the mechanisms leading to liver failure and to determine the utility of interleukin‐6 (IL‐6) administration to improve outcomes. Mice were injected with Chinese hamster ovary cells expressing human IL‐6 or no recombinant protein, or were administered recombinant IL‐6 or carrier by osmotic mini‐pump. Mice were then subjected to 70% or 87% hepatectomy. Light and electron microscopy of liver sections after 87% hepatectomy showed ballooning hepatocytes, vacuolar changes, and mitochondrial abruption, with absence of anoikic nuclei. No significant activation of executor caspases or DNA laddering was observed, although a dramatic decrease in cellular adenosine triphosphate (ATP) stores was measured, suggesting cell death was by a necrotic pathway involving mitochondrial dysfunction. A large increase in protein oxidation was observed, indicative of significant oxidative stress. IL‐6 treatment before 87% hepatectomy resulted in less biochemical and histological evidence of liver injury as well as earlier proliferating chain nuclear antigen (PCNA) expression and accelerated recovery of liver mass. IL‐6 pretreatment induced the antioxidative injury proteins, ref‐1 and GPX1, decreased protein oxidation, vacuolar changes and leakage of mitochondrial products, improved ATP stores, and maintained cellular ultrastructure after 87% hepatectomy. Conclusion: Massive oxidative injury and mitochondrial dysfunction occurs in the liver after extreme hepatectomy. IL‐6 improves recovery and survival from extreme liver resection by enhancing pro‐growth pathways, reducing oxidative stress, and maintaining mitochondrial function. (HEPATOLOGY 2007.)