Hepatic ischemia reperfusion (IR) injury is a major clinical problem during the perioperative period and occurs frequently after major hepatic resection or liver transplantation. Exogenous and endogenous A1 adenosine receptor (A1AR) activation protects against renal IR injury. In this study, we questioned whether exogenous and endogenous A1AR activation protects against hepatic IR injury in vivo. A1AR wild-type (WT) or knockout mice were subjected to 60 minutes of partial hepatic IR. Some animals were treated with a selective A1AR agonist, 2-chloro-N6-cyclopentyladenosine (CCPA; 0.1 mg/kg), or a selective A1AR antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 0.4 mg/kg), 15 minutes before hepatic ischemia. Twenty-four hours after hepatic IR, the A1 knockout mice and DPCPX-treated A1 wild-type (A1WT) mice developed significantly worse liver injury (alanine aminotransferase, liver necrosis, neutrophil infiltration, and apoptosis) compared to A1AR WT mice. However, the selective A1AR agonist CCPA failed to protect against hepatic IR injury in A1WT mice. Our results show that the endogenous A1ARs protect against hepatic IR injury in vivo by primarily reducing apoptosis and necrosis with subsequent reductions in proinflammatory neutrophil infiltration. However, in contrast to the kidneys, in which exogenous A1AR activation protected against IR injury, exogenous A1AR activation failed to protect against liver injury after IR. We conclude that endogenous A1AR activation prevents worsened murine liver IR injury primarily by reducing necrotic and apoptotic cell death. Harnessing the mechanisms of cytoprotection with endogenous A1AR activation may lead to new therapies for perioperative hepatic IR injury. Liver Transpl, 2008. © 2008 AASLD.