Background: Dynamic regulation of respiratory ciliary beat frequency (CBF) is regulated by fluxes in intracellular calcium (Ca2+). P2X receptors (P2XR) are extracellular ATP-gated, Ca2+-permeable, nonselective cation channels. Zinc increases intracellular Ca2+ in a sodium (Na+)-free environment through activation of P2XR channels. We hypothesize that topical zinc increases CBF in a Ca2+-dependent fashion as a result of this mechanism. Methods: The apical surface of mouse sinonasal air-liquid interface cultures were bathed in zinc in a Na +-free solution with or without Ca2+. High-speed digital video imaging captured and analyzed CBF at a sampling rate of 100 frames/s. Results: CBF significantly increased fourfold over baseline from 5.99 ± 3.16 Hz to 22.4 ± 4.33 Hz in the presence of zinc chloride (50 micromoles) and calcium chloride (3 mM). This effect is abolished in the presence of extracellular Na+ and was pH dependent. Conclusion: Zinc stimulates CBF in the presence of Ca2+ likely through activation of P2X receptors. Thus, zinc represents a promising agent for stimulation of mucociliary clearance. Copyright © 2010, Oceanside Publications, Inc.