Ischemia and reperfusion during renal transplant and aortic surgery result in renal ischemic-reperfusion injury. Previously, we showed that preischemic adenosine treatment protects renal function via A(1) adenosine receptor (AR) activation. In contrast, in the cardiac and pulmonary systems, postischemic adenosine has potent anti-inflammatory attributes and is protective against reperfusion injury via activation of A(2a) ARs. We questioned whether adenosine given after an ischemic insult protects renal function in rats, and we sought to determine the AR subtype and intracellular second messengers involved. Rats were randomized to a sham operation, 45 minutes of renal ischemia and reperfusion and treatments with systemic adenosine or selective AR agonists and antagonists, or treatments of dibutyryl cyclic adenosine monophosphate (cAMP) after 45 minutes of renal ischemia but before reperfusion. Forty-five minutes of renal ischemia followed by 24 hours of reperfusion led to severe renal dysfunction as indicated by marked rises in creatinine and histologically evident renal tubular damage. Adenosine treatment after ischemia protected renal function and improved tubular histology. This protection was mediated via A(2a) AR activation because the A(2a)-selective AR agonist [4-((N-ethyl-5'-carbamoyadenos-2-yl)-aminoethyl)-phenylpropionic acid (CGS-21680)] mimics adenosine-induced renal protection, and the A(2a)-selective AR antagonist [8-(3-chlorostyryl)caffeine (CSC)] blocks adenosine-induced renal protection. A(1) or A(3) AR agonists and antagonists did not mimic and block adenosine-induced renal protection. The signaling intermediates of A(2a) AR-mediated renal protection appear to include cAMP because dibutyryl cAMP mimicked adenosine and CGS-21680 mediated renal protection. Rat kidneys can be protected against reperfusion injury via postischemic A(2a) AR activation or cAMP. These data suggest that A(2a) adenosine agonists may have clinically beneficial implications when renal ischemia is unavoidable.