It has been proposed that defective submucosal gland function in CF airways is a major determinant of CF airway disease. We tested the hypothesis that submucosal gland function is defective early in CF subjects with minimal clinical disease. Functional assays of gland fluid secretion rate and viscosity were performed on freshly obtained nasal biopsies from 6 CF subjects and 5 non-CF controls (age range 2-22 years). Secretions from individual submucosal glands were visualized by light/fluorescence microscopy after orienting and immobilizing biopsy specimens in a custom chamber. The viscosity of freshly secreted gland fluid after pilocarpine, measured by fluorescence recovery after photobleaching of microinjected FITC-dextran, was 4.9 +/- 0.2- vs. 2.2 +/- 0.2-fold greater than water viscosity in CF vs. non-CF specimens, respectively (SE, P<10(-4)). Gland fluid secretion rate in CF specimens, measured by video imaging (4.5+/-0.5 nL/min/gland, n=6), was 2.7-fold reduced compared to non-CF specimens (n=3, P<0.05). Quantitative histology revealed similar size and morphology of submucosal glands in CF and non-CF specimens. Our results suggest that defective airway submucosal gland function is an early, primary defect in CF. Therapies directed at normalizing gland fluid secretion early in CF may thus reduce lung disease.