It is well established that liver ischemia/reperfusion induces the expression of HSP70. However, the biological function of HSP70 in this injury is unclear. In this study, we sought to determine the role of HSP70 in hepatic ischemia/reperfusion injury in mice. Male mice were subjected to 90 minutes of partial hepatic ischemia followed by up to 8 hours of reperfusion. HSP70 was rapidly upregulated after reperfusion. To explore the function of HSP70, sodium arsenite (8 mg/kg, i.v.) was injected prior to surgery. We found that this dose induced HSP70 expression within 6 hours of treatment. Induction of HSP70 with arsenite resulted in a >50% reduction in liver injury as determined by serum transaminases and histology. In addition, arsenite similarly reduced liver neutrophil recruitment, liver NF-B activation, and attenuated serum levels of TNF and MIP-2, but increased levels of IL-6. In HSP70-knockout mice, arsenite did not protect against liver injury but did reduce liver neutrophil accumulation. Arsenite-induced reductions in neutrophil accumulation in HSP70-knockout mice were found to be mediated by IL-6. To determine whether extracellular HSP70 contributed to the injury, recombinant HSP70 was injected prior to surgery. Intravenous injection of 10µg of recombinant HSP70 had no effect on liver injury after ischemia/reperfusion. The data suggest that intracellular HSP70 is directly hepatoprotective during ischemia/reperfusion injury and that extracellular HSP70 is not a significant contributor to the injury response in this model. Targeted induction of HSP70 may represent a potential therapeutic option for post-ischemic liver injury.