Adenosine is generated at sites of tissue injury where it serves to regulate inflammation and damage. Adenosine signaling has been implicated in the regulation of pulmonary inflammation in diseases such as asthma and chronic obstructive pulmonary disease; however, the contribution of specific adenosine receptors to key immunoregulatory processes in these diseases is unclear. Mice deficient in the enzyme adenosine deaminase (ADA) develop pulmonary inflammation and mucous metaplasia in association with adenosine elevations making them a useful model for assessing the contribution of specific adenosine receptors to adenosine-mediated pulmonary disease. Studies suggest that the A_2A adenosine receptor (A_2AR) functions to limit inflammation and promote tissue protection; however, the contribution of A_2AR signaling has not been examined in the ADA-deficient model of adenosine-mediated lung inflammation. The purpose of this study was to examine the contribution of A_2AR signaling to the pulmonary phenotype seen in ADA-deficient mice. This was accomplished by generating ADA/A_2AR double knockout mice. Genetic removal of the A_2AR from ADA-deficient mice resulted in enhanced inflammation comprised largely of macrophages and neutrophils, mucin production in the bronchial airways and angiogenesis, relative to that seen in the lungs of ADA-deficient mice with the A_2AR. In addition, levels of the chemokines MCP-1 and CXCL1 were elevated, whereas levels of cytokines such as TNF- and IL-6 were not. There were no compensatory changes in the other adenosine receptors in the lungs of ADA/A_2AR double knockout mice. These findings suggest that the A_2AR plays a protective role in the ADA-deficient model of pulmonary inflammation.