A denosine has been described as playing a role in the control of inflammation, but it has not been certain which of its receptors mediate this effect. Here, we generated an A_2B adenosine receptor–knockout/reporter gene–knock-in (A_2BAR-knockout/reporter gene–knock-in) mouse model and showed receptor gene expression in the vasculature and macrophages, the ablation of which causes low-grade inflammation compared with age-, sex-, and strain-matched control mice. Augmentation of proinflammatory cytokines, such as TNF-α, and a consequent downregulation of IκB-α are the underlying mechanisms for an observed upregulation of adhesion molecules in the vasculature of these A_2BAR-null mice. Intriguingly, leukocyte adhesion to the vasculature is significantly increased in the A_2BAR-knockout mice. Exposure to an endotoxin results in augmented proinflammatory cytokine levels in A_2BAR-null mice compared with control mice. Bone marrow transplantations indicated that bone marrow (and to a lesser extent vascular) A_2BARs regulate these processes. Hence, we identify the A_2BAR as a new critical regulator of inflammation and vascular adhesion primarily via signals from hematopoietic cells to the vasculature, focusing attention on the receptor as a therapeutic target.