Problem Epithelial ion transport regulates hydration of respiratory mucosal surfaces, which promotes effective mucociliary clearance. Activators of chloride ion (Cl-) secretion, such as ascorbic acid (Vitamin C), may enhance the rheologic properties of mucus. Altered ion transport could play a role in the pathogenesis of chronic rhinosinusitis (CRS). The purpose of this study is to assess the electrophysiologic characteristics and role of vitamin C on the nasal mucosa of CRS patients. Methods Nasal tissues (uncinate process, inferior turbinate, nasal septum) were obtained from five CRS patients during sinus surgery and mounted on disks with open areas of 0.03cm2 to 0.71cm2 between Ussing hemichambers. Short-circuit current (Isc) was continuously recorded, and at 50-s intervals transepithelial voltage was clamped from 0 to 2mV. Serosa-to-mucosa-directed Cl- gradient was applied to increase the electrochemical driving force for Cl- exit across the apical membrane. Results Isc decreased when the epithelial Na+ channel blocker (amiloride) was added to the luminal side of the chamber indicating that the tissues were Na+ absorbing. Addition of the cAMP-elevating agonist forskolin induced a Cl- secretory response and exposure of the apical airway surface to vitamin C(600uM) stimulated the transepithelial Cl- secretion to 60% of the forskolin-stimulated Isc. The contribution of the Na+/K+/2Cl- cotransporter to the Cl- secretory response was verified by addition of bumetamide. Glybenclamide was used to probe for the CFTR-Cl- conductance. These results were observed in all specimens. Conclusion Freshly excised human nasal epithelium is easily accessible and its bioelectric measurements can be applied as a functional measurement of ion transport in epithelial diseases. Vitamin C may serve as a biological regulator of CFTR-mediated Cl- secretion in human nasal epithelia. Significance Vitamin C in human nasal epithelia may represent a potential target for the complementary treatment of thickened mucus secretions by enhancing epithelial fluid secretion in diseases, such as CRS or cystic fibrosis.