Mucociliary clearance is determined by ciliary activity and rheology of airway surface liquid. To test the hypothesis that mucociliary clearance would increase after inhalation of an osmotically active agent that would increase the volume of airway surface liquid, we measured mucociliary clearance in 16 normal subjects after inhalation of varying tonicities of saline alone, and after pretreatment with a Na+ channel blocker (amiloride). Subjects inhaled vehicle (0.12% saline) or amiloride, followed by inhalation of 0.12, 0.9, or 7% saline. Subsequently, mucociliary clearance rates were measured by gamma scintigraphy of inhaled 99mTc Fe2O3. Mucociliary clearance of whole and peripheral lung was increased (approximately twofold) after inhalation of increasing concentrations of saline (p < 0.04). Pretreatment with amiloride increased mucociliary clearance rates (approximately twofold) after inhalation of 0.12 and 0.9% saline (p < 0.05), but not 7% saline. The rates of mucociliary clearance by pretreatment with amiloride and 7% saline alone (approximately 1.4% per minute) approached the rapid mucociliary clearance rates (approximately 2.0% per minute) reported in systemic pseudohypoaldosteronism, which has loss-of-function mutations of the epithelial Na+ channel and an increased volume of airway surface liquid. We conclude that maneuvers that increase the volume of airway surface liquid are associated with increased rates of mucociliary clearance in normal subjects.