Background: The cationic antimicrobial peptide lysozyme is the most prevalent innate immune protein in nasal secretions but there is a paucity of research regarding its role in paranasal sinus disease. Lysozyme is generally regarded as an antibacterial agent; however, some data suggest activity toward yeast. This study was designed to determine if lysozyme displays fungicidal activity toward fungi commonly identified in patients with chronic rhinosinusitis (CRS) or fungal sinusitis. Methods: Using a colony-forming unit assay the fungicidal activity of lysozyme (0, 0.5, 5, and 50 micromolar; 0- to 7-hour treatment) was tested against strains of Aspergillus fumigatus, the yeast Candida albicans, and other fungi commonly identified in mucin of patients with CRS. Fungi cultured directly from the mucin of two CRS patients were also tested to determine if they were resistant to the fungicidal activity of lysozyme. Results: The fungicidal effect of lysozyme was both concentration and time dependent. After 7-hour treatment lysozyme (5 micromolar) had >80% fungicidal activity against A. fumigatus, Penicillium sp., Acremonium sp., C. albicans, and Candida parapsilosis. The fungicidal activity of lysozyme toward Alternaria alternata could not be determined. Lysozyme was also fungicidal toward the clinical isolates A. fumigatus and Aspergillus terreus cultured from the mucin of CRS patients. Conclusion: Lysozyme displays fungicidal activity toward many fungi commonly identified in patients with CRS, as well as clinical fungi isolates cultured from the mucin of CRS patients. Additional studies are required to determine the regulation of lysozyme in CRS.