Rationale: Mast cells and neutrophils are key contributors to the pathophysiological inflammatory processes that underpin asthma and chronic obstructive pulmonary disease (COPD), partly through release of noxious serine proteases, including cathepsin G and chymase. From this standpoint, a dual inhibitor of neutrophil cathepsin G and mast cell chymase could protect against these disease-related inflammatory responses. Objectives: We examined the anti-inflammatory pharmacology of RWJ-355871, a dual inhibitor of cathepsin G and chymase, in animal models of inflammation that evince pathophysiological pathways relevant to asthma and COPD to determine the therapeutic potential of this compound. Methods: In an ovalbumin-sensitized rat model, RWJ-355871 was administered to block the mast cell-mediated increase in paw volume caused by ovalbumin injection. In a sheep asthma model, antigen-induced airway responses were assessed with and without aerosol treatment with RWJ-355871. In a murine tobacco-smoke model of airway inflammation, the effect of RWJ-355871 on smoke-induced neutrophilia was determined. Measurements and Main Results: Intravenous treatment of ovalbumin-sensitized rats with RWJ-355871 provided dose-dependent reduction in the increase in rat paw volume. In allergic sheep, aerosol pretreatment with RWJ-355871 showed dose-dependent inhibition of the antigen-induced early response, late response, and post-antigen-induced airway hyperreponsivenss. In tobacco smoke-exposed mice, nebulized RWJ-355871 significantly reduced the smoke-induced neutrophilia observed in untreated mice. Conclusions: The preclinical anti-inflammatory effects of RWJ-355871 in these animal models of inflammation indicate that this dual inhibitor may have therapeutic utility for treating airway inflammatory diseases involving mechanisms that depend on cathepsin G and/or chymase.