Oncostatin M (OSM) is a member of the IL‐6 family of cytokines. Mice deficient in the OSM receptor (OSMR^‐/‐) showed impaired liver regeneration with persistent parenchymal necrosis after carbon tetrachloride (CCl₄) exposure. The recovery of liver mass from partial hepatectomy was also significantly delayed in OSMR^‐/‐ mice. In contrast to wildtype mice, CCl₄ administration only marginally induced expression of tissue inhibitor of metalloproteinase (TIMP)‐1 and TIMP‐2 genes in OSMR^‐/‐ mice, correlating with the increased gelatinase activity of matrix metalloproteinase (MMP)‐9 and matrix degradation in injured livers. The activation of STAT3 and expression of immediate early genes and cyclins were decreased in OSMR^‐/‐ liver, indicating that OSM signaling is required for hepatocyte proliferation and tissue remodeling during liver regeneration. We also found that CCl₄ administration in IL‐6^‐/‐ mice failed to induce OSM expression and that OSM administration in IL‐6^‐/‐ mice after CCl₄ injection induced the expression of cyclin D1 and proliferating cell nuclear antigen, suggesting that OSM is a key mediator of IL‐6 in liver regeneration. Consistent with these results, administration of OSM ameliorated liver injury in wildtype mice by preventing hepatocyte apoptosis as well as tissue destruction. In conclusion, OSM and its signaling pathway may provide a useful therapeutic target for liver regeneration. (HEPATOLOGY 2004;39:635–644.)