Proteinase-Activated rreceptor-2 (PAR ₂ ), a G-protein–coupled Receptor, activated by serine proteinases, is reported to have both protective and proinflammatory effects in the airway. Given these opposing actions, both inhibitors and activators of PAR ₂ have been proposed for treating asthma. PAR ₂ can signal through two independent pathways: a β-arrestin–dependent one that promotes leukocyte migration, and a G-protein/Ca ²⁺ one that is required for prostaglandin E ₂ (PGE ₂ ) production and bronchiolar smooth muscle relaxation. We hypothesized that the proinflammatory responses to PAR ₂ activation are mediated by β-arrestins, whereas the protective effects are not. Using a mouse ovalbumin model for PAR ₂ -modulated airway inflammation, we observed decreased leukocyte recruitment, cytokine production, and mucin production in β-arrestin-2 ^−/− mice. In contrast, PAR ₂ -mediated PGE ₂ production, smooth muscle relaxation, and decreased baseline airway resistance (measures of putative PAR ₂ “protective” effects) were independent of β-arrestin-2. Flow cytometry and cytospins reveal that lung eosinophil and CD4 T-cell infiltration, and production of IL-4, IL-6, IL-13, and TNFα, were enhanced in wild-type but not β-arrestin-2 ^−/− mice. Using the forced oscillation technique to measure airway resistance reveals that PAR ₂ activation protects against airway hyperresponsiveness by an unknown mechanism, possibly involving smooth muscle relaxation. Our data suggest that the PAR ₂ -enhanced inflammatory process is β-arrestin-2 dependent, whereas the protective anticonstrictor effect of bronchial epithelial PAR ₂ may be β-arrestin independent.