Pharmacological evidence suggests that activation of A_2B adenosine receptors results in pro-inflammatory effects relevant to the progression of asthma, a chronic lung disease associated with elevated interstitial adenosine concentrations in the lung. This concept has been challenged by the finding that genetic removal of A_2B receptors leads to exaggerated responses in models of acute inflammation. Therefore, the goal of our study was to determine the effects of A_2B receptor gene ablation in the context of ovalbumin-induced chronic pulmonary inflammation. We found that repetitive airway allergen challenge induced a significant increase in adenosine levels in fluid recovered by bronchoalveolar lavage (BAL). Genetic ablation of A_2B receptors significantly attenuated allergen-induced chronic pulmonary inflammation as evidenced by a reduction in the number of BAL eosinophils and in peribronchial eosinophilic infiltration. The most striking difference in the pulmonary inflammation induced in A_2BKO and wild-type mice was the lack of allergen-induced IL-4 release in the airways of A_2BKO animals, in line with a significant reduction in IL-4 protein and mRNA levels in lung tissue. In addition, attenuation of allergen-induced transforming growth factor-beta release in airways of A_2BKO mice correlated with reduced airway smooth muscle and goblet cell hyperplasia/hypertrophy. In conclusion, genetic removal of A_2B adenosine receptors in mice leads to inhibition of allergen-induced chronic pulmonary inflammation and airway remodeling. These findings are in agreement with previous pharmacological studies suggesting a deleterious role for A_2B receptor signaling in chronic lung inflammation.