Asthma is a chronic pulmonary disease that affects over 150 million people worldwide and over 17 million in the United States alone. In asthma, chronic inflammation causes an associated increase in airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning (ref. 2). The pathophysiology of asthma is typically described as chronic inflammation in the airways, dominated primarily by the Helper T-Cell 2 (Th2) inflammatory response. This response is characterized by eosinophilic infiltration into the airway smooth muscle cells but also mast cells, macrophages, plasma cells, and neutrophils may be present (ref. 1). Another hallmark characteristic of asthma is airway remodeling which encompasses structural changes in the airway wall as a result of lung responses to damage from inflammatory events (ref. 1). To counter these effects, the protein C (PC) pathway, intervenes by exerting anti-inflammatory and anticoagulant effects. PC interacts with Endothelial Cell Protein C Receptor (EPCR) which is an endothelial transmembrane glycoprotein that is expressed on the luminal surface of the endothelium. When PC binds to EPCR, it enhances the activation of PC to aPC by thrombin/thrombomodulin, by at least 20-fold (ref. 26). Therefore, it has been proposed that EPCR may contribute to the anti-inflammatory effects of aPC. The current study examined the role of EPCR in mice challenged with the inflammatory agent ovalbumin (OVA). EPCRÌ_å«/Ì_å« (EPCR very low-expressing mice) and wild-type (WT) mice were utilized for this study. While the airway hyperresponsiveness to OVA challenge in WT and EPCRÌ_å«/Ì_å« mice were similiar, examination of bronchioalveolar lavage fluid (BALF), lung tissue, and circulating blood showed significantly higher levels of eosinophils in EPCRÌ_å«/Ì_å« mice versus WT mice, and significantly higher levels of eotaxin and Interleukin-13. The TH2 cell response from isolated peribronchial lymph nodes in EPCRÌ_å«/Ì_å« mice showed significantly elevated Interleukin-5 levels. Bronchial epithelial cell adenovirus-12 SV40 hybrid virus transformed cells (BEAS-2B), a human epithelial cell line, when stimulated with BALF from WT and EPCRÌ_å«/Ì_å« mice, showed higher eotaxin message ribonucleic acid (mRNA) production in the EPCRÌ_å«/Ì_å« mice. Results from this study indicate that a deficiency in EPCR increases the inflammatory response in a murine model of OVA-induced asthma.