Proteinase-activated receptor-2 (PAR 2) is expressed by different types of human leukocytes and involved in the development of inflammatory and infectious diseases. However, its precise role in the regulation of human monocyte and macrophage function during viral infection remains unclear. Also, the ability of PAR 2 agonists to enhance the effects induced by immune mediators during infection or inflammation is still poorly investigated. Therefore, we investigated the ability of a PAR 2 agonist to enhance IFN-γ-induced suppression of influenza A virus replication in human monocytes. We found that this effect correlates with an increased abundance of IκBα after costimulation of cells with PAR 2 agonist and IFN-γ. Remarkably, coapplication of PAR 2 agonist and IFN-γ also enhances the effects of IFN-γ on IFN-γ-inducible protein 10 kDa release, and CD64 and αVβ3 surface expression by human monocytes. Together, these findings indicate a potentially protective role of PAR 2 activation during the progression of influenza A virus infection. This effect could be associated with the ability of PAR 2 agonists to enhance IFN-γ-induced protective effects on human monocytes.