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Introduction: Hepatocellular injury caused by ischemia-reperfusion of the liver occurs in a number of clinical situations including major trauma, elective surgery of the liver, and liver transplantation. Several strategies have been used to prevent liver injury following ischemia-reperfusion (I/R). Among these, ischemic preconditioning has shown promise as a preventative approach. In this manuscript, we hypothesized that use of remote ischemic preconditioning by brief hindlimb ischemia might prevent liver dysfunction in a mouse model of liver I/R., Methods: C57/B mice were subjected to 60 minutes of partial liver ischemia with or without antecedent hindlimb vascular I/R. Blood was drawn for serum alanine aminotransferase levels at times following liver reperfusion. Liver inflammation was assessed by measuring serum and liver tumor necrosis factor (TNF)-alpha protein and mRNA. The role of toll-like receptor 4 (TLR4) in mediating protection was determined using the mouse strain HeJ, which has a mutated TLR4., Results: Antecedent hindlimb ischemia (10 minutes) lessened I/R-induced elevation of serum alanine aminotransferase compared with untreated I/R animals. This protection correlated with a reduction in serum TNF-alpha protein levels as well as liver TNF-alpha mRNA and apoptosis. High Mobility Group-Box 1 (HMG-B1) levels in the blood were elevated after hindlimb ischemia and injection of HMG-B1 prior to liver recapitulated the protective effect of hindlimb occlusion. TLR4-mutant HeJ mice did not demonstrate protection with hindlimb preconditioning., Conclusions: Brief hindlimb occlusion prevents liver I/R injury. This effect appears to be related to release of HMG-B1 and is dependent on the presence of a functional TLR4. Remote ischemia preconditioning represents a novel approach to preventing distant organ injury.