Inactivation of the adenosine A_2A receptor (A_2AR) consistently protects against ischemic brain injury and other neural insults, but the relative contribution of A_2ARs on peripheral inflammatory cells versus A_2ARs expressed on neurons and glia is unknown. We created a chimeric mouse model in which A_2ARs on bone marrow–derived cells (BMDCs) were selectively inactivated or reconstituted by bone marrow transplantation. Selective reconstitution of A_2ARs on BMDCs (A_2AR knockout mice transplanted with wild-type bone marrow cells) largely reinstates ischemic brain injury in global A_2AR knockout mice. Conversely, selective inactivation of A_2ARs on BMDCs (wild-type mice transplanted with A_2AR knockout bone marrow cells) attenuates infarct volumes and ischemia-induced expression of several proinflammatory cytokines in the brain, but exacerbates ischemic liver injury. These results indicate that the A_2AR-stimulated cascade in BMDCs is an important modulator of ischemic brain injury and that ischemic brain and liver injuries are regulated distinctly by A_2ARs on BMDCs.