A_2A adenosine receptors (A_2A-ARs) are known modulators of renal hemodynamics and potent inhibitors of inflammation. We sought to determine whether selective activation of A_2A-ARs protects kidneys from ischemia-reperfusion injury. The ester derivative of DWH-146 (DWH-146e), a selective A_2A agonist, was found to be more potent and selective for A_2A-ARs than the prototype compound CGS-21680. Osmotic minipumps were implanted subcutaneously to infuse into rats either vehicle or DWH-146e (0.004 μg ⋅ kg⁻¹ ⋅ min⁻¹), during and after ischemia-reperfusion injury. Following 24 and 48 h of reperfusion, the rise in serum creatinine and blood urea nitrogen for vehicle-treated rats was substantially elevated compared with DWH-146e-treated rats. Histological examination revealed widespread tubular epithelial necrosis and vascular congestion in the outer medulla of vehicle-treated compared with DWH-146e-treated animals. ZM-241385, a selective A_2A antagonist, blocked the protective effect of DWH-146e. Delaying administration of DWH-146e until the initiation of reperfusion also decreased serum creatinine. We conclude that 1) selective A_2A-AR activation by DWH-146e reduces ischemia-reperfusion injury in rat kidneys,2) the effect of DWH-146e is A_2A receptor mediated, and3) the protective effects are mediated by preventing injury during the reperfusion period.