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Background —The mechanism of delayed preconditioning induced by activation of adenosine A 1 receptors (A 1 ARs) is not fully understood. We determined the role of inducible nitric oxide synthase (iNOS) in mediating adenosine-induced late cardioprotection using pharmacological inhibitors and iNOS gene–knockout mice. Methods and Results —Adult male mice were treated with saline or an A 1 AR agonist, 2-chloro- N 6 -cyclopentyladenosine (CCPA). Twenty-four hours later, the hearts were perfused in Langendorff mode and subjected to 30 minutes of global ischemia followed by 30 minutes of reperfusion. 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX; 0.1 mg/kg IP) and S -methylisothiourea (SMT; 3 mg/kg IP) were used to block A 1 ARs and iNOS, respectively. Infarct size (IS) was measured by triphenyltetrazolium chloride staining, and iNOS expression was measured by Western blots. Myocardial IS was reduced from 24.0±3.2% in the saline group to 12.2±2.5% in CCPA-treated mice ( P Conclusions —Selective activation of A 1 ARs produces delayed cardioprotection against ischemia/reperfusion injury in the mouse. Increased iNOS expression concomitant with the lack of protective effect of A 1 AR activation in iNOS gene–knockout mice suggests a direct cause-and-effect relationship of iNOS in adenosine-induced late cardioprotection.