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 A 1 adenosine receptor (A 1 AR) activation protects against renal IR injury. In this study, we questioned whether exogenous and endogenous A 1 AR activation protects against hepatic IR injury in vivo. A 1 AR wild-type (WT) or knockout mice were subjected to 60 minutes of partial hepatic IR. Some animals were treated with a selective A 1 AR agonist, 2-chloro-N 6 -cyclopentyladenosine (CCPA; 0.1 mg/kg), or a selective A 1 AR antagonist, 8-cyclopentyl-1,3dipropylxanthine (DPCPX; 0.4 mg/kg), 15 minutes before hepatic ischemia. Twenty-four hours after hepatic IR, the A 1 knockout mice and DPCPX-treated A 1 wild-type (A 1 WT) mice developed significantly worse liver injury (alanine aminotransferase, liver necrosis, neutrophil infiltration, and apoptosis) compared to A 1 AR WT mice. However, the selective A 1 AR agonist CCPA failed to protect against hepatic IR injury in A 1 WT mice. Our results show that the endogenous A 1 ARs 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 A 1 AR activation protected against IR injury, exogenous A 1 AR activation failed to protect against liver injury after IR. We conclude that endogenous A 1 AR activation prevents worsened murine liver IR injury primarily by reducing necrotic and apoptotic cell death. Harnessing the mechanisms of cytoprotection with endogenous A 1 AR activation may lead to new therapies for perioperative hepatic IR injury.