Background: Oleoylethanolamide (OEA), an endogenously generated cannabinoid-like compound, has been reported to be increased in patients with severe asthma and aspirin-exacerbated respiratory disease. Recruitment of activated eosinophils in the airways is a hallmark of bronchial asthma. Objective: To explore the direct contribution of cannabinoid receptor 2 (CB2), a cognate receptor of OEA, which induces of eosinophil activation in vitro and in vivo. Methods: We investigated OEA signaling in the eosinophilic cell line dEol-1, in peripheral blood eosinophils from asthmatics. In order to confirm whether eosinophil activation by OEA is CB2 dependent or not, CB2 siRNA and the CB2 antagonist SR144528 were used. The numbers of airway inflammatory cells and the levels of cytokines were measured in bronchoalveolar lavage fluid, and airway hyper-responsiveness were examined in the BALB/c mice. Results: CB2 expression was increased after OEA treatment in both peripheral blood eosinophils and dEol-1 cells. It was also elevated after OEA-induced recruitment of eosinophils to the lungs in vivo. However, SR144528 treatment reduced the activation of peripheral blood eosinophils from asthmatic patients. Furthermore, CB2 knockdown decreased the activation of dEol-1 cells and the levels of inflammatory and T2 cytokines. SR144528 treatment alleviated airway hyper-responsiveness and eosinophil recruitment to the lungs in vivo. Conclusion: These results suggest that CB2 may contribute to the pathogenesis of eosinophilic asthma. Our results provide a new insight into the molecular mechanism of signal transduction by OEA in eosinophilic asthma.Keywords: CB2 receptor; asthma; endocannabinoid; eosinophils; oleoylethanolamide.