Interleukin‐6 (IL‐6) is an important mediator of liver regeneration and repair that is also elevated in chronic liver diseases, including fatty liver of obesity and cirrhosis. IL‐6 has been reported both to delay and accelerate liver regeneration. We examined the effects on liver injury and regeneration of a continuous administration of exogenous IL‐6 to mice by injection of an IL‐6–expressing CHO‐cell line in athymic nude mice and by osmotic mini‐pump delivery of recombinant murine IL‐6. Short‐term IL‐6 administration (1‐2 days) accelerated early recovery of liver mass, whereas more long‐term administration (5‐7 days) markedly impaired liver regeneration. Similarly, short‐term IL‐6 treatment increased hepatic resistance to the lethal effects of the Fas agonist Jo‐2, but on more prolonged IL‐6 exposure the Jo‐2 resistance vanished. IL‐6 administration initially induced expression of the anti‐apoptotic proteins Bcl‐2 and Bcl‐x_L, correlating with protection against Fas‐mediated cell death. More prolonged IL‐6 administration, however, resulted in marked induction of the pro‐apoptotic protein Bax. This result coincided with increased activation of the type II or intrinsic, mitochondrial path to cell death, manifested by increased caspase‐9 activation and increased cytochrome c release after Jo‐2 exposure. These data demonstrate that IL‐6 can function acutely to improve hepatic regeneration and repair, but that more chronic exposure not only abolishes the protective effects of IL‐6, but actually sensitizes the liver to injury and death. In conclusion, elevated IL‐6 in certain chronic liver diseases contributes to an increased likelihood of liver failure after injury. (HEPATOLOGY 2006;43:474–484.)