Despite intensive research, efforts to reduce the mortality of septic patients have failed. Adenosine is a potent extracellular signaling molecule, and its levels are elevated in sepsis. Adenosine signals through G-protein–coupled receptors and can regulate the host’s response to sepsis. In this study, we studied the role of A 2B adenosine receptors in regulating the mortality and inflammatory response of mice following polymicrobial sepsis. Genetic deficiency of A 2B receptors increased the mortality of mice suffering from cecal ligation and puncture-induced sepsis. The increased mortality of A 2B knockout mice was associated with increased levels of inflammatory cytokines and chemokines and augmented NF-κB and p38 activation in the spleen, heart, and plasma in comparison with wild-type animals. In addition, A 2B receptor knockout mice showed increased splenic apoptosis and phosphatase and tensin homolog activation and decreased Akt activation. Experiments using bone-marrow chimeras revealed that it is the lack of A 2B receptors on nonhematopoietic cells that is primarily responsible for the increased inflammation of septic A 2B receptor-deficient mice. These results indicate that A 2B receptor activation may offer a new therapeutic approach for the management of sepsis.