Ischemia-reperfusion (I/R) injury occurs as a result of restoring blood flow to previously hypoperfused vessels or after tissue transplantation and is characterized by inflammation and microvascular occlusion. We report here that 4-[3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl]-cyclohexanecarboxylic acid methyl ester (ATL146e), a selective agonist of the A(2A) adenosine receptor (A(2A)AR), profoundly protects mouse liver from I/R injury when administered at the time of reperfusion, and protection is blocked by the antagonist ZM241385. ATL146e lowers liver damage by 90% as assessed by serum glutamyl pyruvic transaminase and reduces hepatic edema and MPO. Most protection remains if ATL146e treatment is delayed for 1 h but disappears when delayed for 4 h after the start of reperfusion. In mice lacking the A(2A)AR gene, protection by ATL1465e is lost and ischemic injury of short duration is exacerbated compared with wild-type mice, suggesting a protective role for endogenous adenosine. I/R injury causes induction of hepatic transcripts for IL-1alpha, IL-1beta, IL-1Ra, IL-6, IL-10, IL-18, INF-beta, INF-gamma, regulated on activation, normal T cell expressed, and presumably secreted (RANTES), major intrinsic protein (MIP)-1alpha, MIP-2, IFN-gamma-inducible protein (IP)-10, and monocyte chemotactic protein (MCP)-1 that are suppressed by administering ATL146e to wild-type but not to A(2A)AR knockout mice. RANTES, MCP-1, and IP-10 are notable as induced chemokines that are chemotactic to T lymphocytes. The induction of cytokines may contribute to transient lymphopenia and neutrophilia that occur after liver I/R injury. We conclude that most damage after hepatic ischemia occurs during reperfusion and can be blocked by A(2A)AR activation. We speculate that inhibition of chemokine and cytokine production limits inflammation and contributes to tissue protection by the A(2A)AR agonist ATL146e.