Hepatic ischemia and reperfusion injury (IRI) remains an important challenge in clinical orthotopic liver transplantation (OLT). Tissue inhibitor of metalloproteinase‐1 (TIMP‐1) is the major endogenous regulator of matrix metalloproteinase‐9 (MMP‐9). In this study we investigated the functional significance of TIMP‐1 expression in a well‐established mouse model of partial liver IRI. Compared to wildtype mice, TIMP‐1^−/− mice showed further impaired liver function and histological preservation after IRI. Notably, TIMP‐1 deficiency led to lethal liver IRI, as over 60% of the TIMP‐1^−/− mice died postreperfusion, whereas all TIMP‐1^+/+ mice recovered and survived surgery. Lack of TIMP‐1 expression was accompanied by markedly high levels of MMP‐9 activity, which facilitates leukocyte transmigration across vascular barriers in hepatic IRI. Indeed, TIMP‐1^−/− livers were characterized by massive leukocyte infiltration and by up‐regulation of proinflammatory mediators, including tumor necrosis factor alpha, interferon‐gamma, and inducible nitric oxide synthase post‐IRI. The inability of TIMP‐1^−/− mice to express TIMP‐1 increased the levels of active caspase‐3 and depressed the expression of Bcl‐2 and the phosphorylation of Akt, emphasizing an important role for TIMP‐1 expression on hepatocyte survival. Using independent parameters of regeneration, 5‐bromodeoxyuridine incorporation, proliferating cell nuclear antigen expression, and histone H3 phosphorylation, we provide evidence that hepatocyte progression into S phase and mitosis was impaired in TIMP‐1‐deficient livers after IRI. Inhibition of the cell cycle progression by TIMP‐1 deficiency was linked to depressed levels of cyclins‐D1 and ‐E and to a disrupted c‐Met signaling pathway, as evidenced by reduced phosphorylated c‐Met expression and elevated c‐Met ectodomain shedding postliver IRI. Conclusion: These results support a critical protective function for TIMP‐1 expression on promoting survival and proliferation of liver cells and on regulating leukocyte recruitment and activation in liver IRI. (HEPATOLOGY 2012;56:1074–1085)