We tested the impact of A 1 adenosine receptor (AR) deletion on injury and oxidant damage in mouse hearts subjected to 25-min ischemia=45-min reperfusion (I=R). Wild-type hearts recovered *50% of contractile function and released 8.2 AE 0.7 IU=g of lactate dehydrogenase (LDH). A 1 AR deletion worsened dysfunction and LDH efflux (15.2 AE 2.6 IU=g). Tissue cholesterol and native cholesteryl esters were unchanged, whereas cholesteryl ester-derived lipid hydroperoxides and hydroxides (CE-O(O)H; a marker of lipid oxidation) increased threefold, and a-tocopherylquinone [a-TQ; oxidation product of a-tocopherol (a-TOH)] increased sixfold. Elevations in a-TQ were augmented by two-to threefold by A 1 AR deletion, whereas CE-O(O)H was unaltered. A 1 AR deletion also decreased glutathione redox status ([GSH]=[GSSG + GSH]) and enhanced expression of the antioxidant response element heme oxygenase-1 (HO-1) during I=R: fourfold elevations in HO-1 mRNA and activity were doubled by A 1 AR deletion. Broad-spectrum AR agonism (10 mM 2-chloroadenosine; 2-CAD) countered effects of A 1 AR deletion on oxidant damage, HO-1, and tissue injury, indicating that additional ARs (A 2A , A 2B , and=or A 3 ) can mediate similar actions. These data reveal that local adenosine engages A 1 ARs during I=R to limit oxidant damage and enhance outcome selectively. Control of a-TOH=a-TQ levels may contribute to A 1 AR-dependent cardioprotection.