Rationale: Previous studies have demonstrated that dysregulated coagulation and fibrinolysis contribute to the pathogenesis of asthma. Objective: The role of procoagulant Factor X in a murine model of ovalbumin-induced asthma was investigated. Methods: Biochemical, cellular, and physiological in vivo and in vitro approaches were utilized to determine effects of Factor X on the asthmatic response in mice. Measurements and Main Results: Factor X transcript levels, as well as Factor Xa activity, were increased in lungs of asthmatic mice challenged with ovalbumin, compared to phosphate-buffered saline-treated controls. Further, Factor X was highly expressed in bronchoalveolar lavage fluid macrophages from asthmatic mice. Treatment of mice with the Factor Xa inhibitor, fondaparinux, during the last 4 wk of ovalbumin challenge, resulted in the attenuation of airway hyperresponsiveness, but did not alter infiltration of inflammatory cells into the lung. However, there was a significant decrease in the thickness of the mucosal layer and in lung collagen deposition in fondaparinux-treated mice. In vitro investigations utilizing human mucus-producing NCI-H292 cells indicated that exogenous Factor Xa enhanced mucin production in a dose-dependent manner. Levels of amphiregulin, a protein that induces mucin production, were also increased in cells stimulated by Factor Xa. Conclusions: The results of this study introduce a novel participant in the asthmatic response, and indicate that Factor Xa functions in airway remodeling in asthma by stimulating mucin production, through regulation of amphiregulin expression and collagen deposition.