BACKGROUND Trefoil factor family (TFF) peptides are mucin-associated secretory products that are produced in the airways and gastrointestinal tract. These peptides appear to play an important role in mucosal healing and epithelial protection and are overexpressed in chronically inflamed gastrointestinal tissues. We hypothesize that TFF peptides may also be differentially expressed in the sinonasal tissue of patients with and without chronic rhinosinusitis (CRS). METHODS Ethmoid sinus tissue was obtained from patients with CRS without nasal polyps (CRSsNP) (n = 12), CRS with nasal polyps (CRSwNP) (n = 12), and nondiseased controls (n = 7). Messenger RNA (mRNA) and protein were extracted from samples and expression of TFF1, TFF2, and TFF3 were assessed using quantitative real-time polymerase chain reaction qRT-PCR and Western blots, respectively. Tissue localization of TFF expression was confirmed using immunohistochemistry. RESULTS TFF1 and TFF3 were both highly expressed in sinonasal tissue, while TFF2 was expressed at near-undetectable levels. CRSsNP tissue had a statistically significant increase in the expression of both TFF1 and TFF3. No difference in TFF expression was found between control and CRSwNP patients. CONCLUSIONS TFF1 and TFF3 are overexpressed in CRSsNP. The role of TFF peptides in mucosal protection and repair suggests a possible important physiologic role in maintaining the sinonasal epithelial barrier and modulating innate immunity in the sinonasal tract.