Anti-microbial treatment strategies need to be improved to reduce the high mortality rates in septic patients. In non-infectious models of acute inflammation, activation of A2A and A2B adenosine receptors (A2AR and A2BR) in extracellular adenosine-rich microenvironments is immunosuppressive. Adenosine regulation of immune cell function through A2ARs and A2BRs is an evolutionarily conserved mechanism to prevent death from inflammation-induced tissue injury/damage due to trauma or infection. The tissue protective role of A2ARs has been shown in liver, cancer, and atherogenic models of tissue inflammation/injury. We examined the roles A2AR and A2BR in anti-bacterial responses in the cecal ligation and puncture (CLP) model of sepsis. Oxygenation (60%) was shown to reduce adenosine levels in cancerous tissue. Oxygen (60%) had the same affect as A2AR/A2AR ablation on enhanced bacterial clearance and sepsis survival. Together this suggests that oxygenation enhances anti-bacterial responses by decreasing extracellular adenosine. In chronically (28 days) infected mice, the absence of A2ARs decreased the presence of bacteria in blood, spleen, and peritoneum. These affects are associated with decreased anti-inflammatory cytokines by the removal of A2AR negative feedback inhibition on pro-inflammatory responses to repeated bacterial challenges. A2BR antagonism significantly increased survival, enhanced bacterial killing, and decreased IL-6 and macrophage inflammatory protein-2 (MIP-2; a CXC chemokine) levels after CLP. A2BR knock-out (KO) mice maintained blood pressure higher than wild type mice within 24 hours and showed an increase in sepsis survival. A2BR deficiency dramatically enhanced bacterial clearance. These affects are explained by better anti-microbial functions of macrophages, including an enhanced killing capacity for E. coli. However, A2BR deficiency did not affect neutrophil phagocytosis of bacteria in vitro. Of potential clinical significance, even late treatment (32 hours post-CLP) with an A2BR antagonist significantly improved survival of mice that were otherwise predicted to die according to plasma IL-6 levels. Thus, our findings of enhanced bacterial clearance and host survival suggest that antagonism of the A2AR- and A2BR-mediated pathways could be a late therapeutic approach for sepsis, to improve phagocytosis of bacteria and survival.