Protease-activated receptor-2 (PAR 2), a receptor highly expressed in the respiratory tract, can influence inflammation at mucosal surfaces. Although the effects of PAR 2 in the innate immune response to bacterial infection have been documented, knowledge of its role in the context of viral infection is lacking. We thus investigated the role of PAR 2 in influenza pathogenesis in vitro and in vivo. In vitro, stimulation of PAR 2 on epithelial cells inhibited influenza virus type A (IAV) replication through the production of IFN-γ. In vivo, stimulation of PAR 2 using specific agonists protected mice from IAV-induced acute lung injury and death. This effect correlated with an increased clearance of IAV in the lungs associated with increased IFN-γ production and a decreased presence of neutrophils and RANTES release in bronchoalveolar fluids. More importantly, the protective effect of the PAR 2 agonist was totally abrogated in IFN-γ-deficient mice. Finally, compared with wild-type mice, PAR 2-deficient mice were more susceptible to IAV infection and displayed more severe lung inflammation. In these mice higher neutrophil counts and increased RANTES concentration but decreased IFN-γ levels were observed in the bronchoalveolar lavages. Collectively, these results showed that PAR 2 plays a protective role during IAV infection through IFN-γ production and decreased excessive recruitment of inflammatory cells to lung alveoli.