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Chronic rhinosinusitis (CRS) is a heterogeneous chronic inflammatory disease of the nose and paranasal sinuses that presents without or with nasal polyps (CRSwNP). Notable features of CRSwNP are the frequent presence of type 2 allergic inflammation and high prevalence of Staphylococcus aureus (SA) colonization. As inflammation persists, sinus tissue undergoes epithelial damage and repair along with polyp growth, despite active medical management. Because one feature of damaged tissue is enhancement of growth factor signaling, we evaluated the presence of epidermal growth factor receptor (EGFR) ligands and matrix metalloproteinases (MMPs) in CRS. The objectives of this study were to analyze the expression of EGFR ligands and MMPs in patients with CRS and to investigate the possible role of SA on epithelial activation. Sinonasal tissues were collected during surgery from control subjects and patients with CRS. Tissues were processed as described previously for analysis of mRNA (RT-PCR) and proteins (ELISA) for the majority of EGFR ligands within the tissue extracts. CRS tissue was used for evaluation of the distribution of epiregulin (EREG), an EGFR ligand, and MMP-1 by immunohistochemistry. In parallel studies, expression of these genes and proteins was analyzed in cultured primary airway epithelial cells. Elevated expression of EREG and MMP-1 mRNA and protein was observed in uncinate and polyp tissue from patients with CRSwNP. Immunohistochemistry study of clinical samples revealed that airway epithelial cells expressed both of these proteins. Cultured primary human airway epithelial cells expressed MMP-1, and MMP-1 was further induced by stimulation with EREG or heat-killed SA (HKSA). The induction of MMP-1 by HKSA was blocked by an antibody against EREG, suggesting that endogenous EREG induces MMP-1 after stimulation with HKSA. EREG and MMP-1 were found to be elevated in nasal polyp and uncinate tissues in patients with CRSwNP. Elevated expression of EREG and MMP-1 may be related to polyp formation in CRS, and colonization of SA might further enhance this process.