The mechanisms governing the impairment of bacterial clearance and immune function in sepsis are not known. Adenosine levels are elevated during tissue hypoxia and damage associated with sepsis. Adenosine has strong immunosuppressive effects, many of which are mediated by A 2A receptors (A 2A R) expressed on immune cells. We examined whether A 2A R are involved in the regulation of immune function in cecal ligation and puncture-induced murine polymicrobial sepsis by genetically or pharmacologically inactivating A 2A R. A 2A R knockout (KO) mice were protected from the lethal effect of sepsis and had improved bacterial clearance compared with wild-type animals. cDNA microarray analysis and flow cytometry revealed increased MHC II expression in A 2A-inactivated mice, suggesting improved Ag presentation as a mechanism of protection. Apoptosis was attenuated in the spleen of A 2A KO mice indicating preserved lymphocyte function. Levels of the immunosuppressive cytokines IL-10 and IL-6 were markedly lower following A 2A R blockade. Similar to observations with A 2A R KO mice, an A 2A R antagonist increased survival even when administered in a delayed fashion. These studies demonstrate that A 2A R blockade may be useful in the treatment of infection and sepsis.