Activation of A_2A adenosine receptors (A_2ARs) protects kidneys from ischemia-reperfusion injury (IRI). A_2ARs are expressed on bone marrow–derived (BM-derived) cells and renal smooth muscle, epithelial, and endothelial cells. To measure the contribution of A_2ARs on BM-derived cells in suppressing renal IRI, we examined the effects of a selective agonist of A_2ARs, ATL146e, in chimeric mice in which BM was ablated by lethal radiation and reconstituted with donor BM cells derived from GFP, A_2AR-KO, or WT mice to produce GFP→WT, A_2A-KO→WT, or WT→WT mouse chimera. We found little or no repopulation of renal vascular endothelial cells by donor BM with or without renal IRI. ATL146e had no effect on IRI in A_2A-KO mice or A_2A-KO→WT chimera, but reduced the rise in plasma creatinine from IRI by 75% in WT mice and by 60% in WT→WT chimera. ATL146e reduced the induction of IL-6, IL-1β, IL-1ra, and TGF-α mRNA in WT→WT mice but not in A_2A-KO→WT mice. Plasma creatinine was significantly greater in A_2A-KO than in WT mice after IRI, suggesting some renal protection by endogenous adenosine. We conclude that protection from renal IRI by A_2AR agonists or endogenous adenosine requires activation of receptors expressed on BM-derived cells.