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Mucociliary clearance (MCC) is the primary physical airway defense against inhaled pathogens and particulates. MCC depends on both proper fluid/ mucus homeostasis and epithelial ciliary beating. Vasoactive intestinal peptide (VIP) is a neurotransmitter expressed in the sinonasal epithelium that is up-regulated in allergy. However, the effects of VIP on human sinonasal physiology are unknown, as are VIP's interactions with histamine, a major regulator of allergic disease. We imaged ciliary beat frequency, mucociliary transport, apical Cl- permeability, and airway surface liquid (ASL) height in primary human sinonasal air-liquid-interface cultures to investigate the effects of VIP and histamine. VIP stimulated an increase in ciliary beat frequency (EC50 0.5 µM; maximal increase -40% compared with control) and cystic fibrosis transmem-brane conductance regulator (CFFR)-dependent and Na+K+2Cl- cotransporter-dependent fluid secretion, all requiring cAMP/PKA signaling. Histamine activated Ca2+ signaling that increased ASL height but not ciliary beating. Low concentrations of VIP and histamine had synergistic effects on CFrR-dependent fluid secretion, revealed by increased ASL heights. An up-regulation of VIP in histamine-driven allergic rhinitis would likely enhance mucosal fluid secretion and contribute to allergic rhinorrhea. Conversely, a loss of VIP-activated secretion in patients with CF may impair mucociliary transport, contributing to increased incidences of sino-nasal infections and rhinosinusitis. [ABSTRACT FROM AUTHOR]