Nonadrenergic, noncholinergic nerves are the predominant inhibitory nervous pathway in human airway smooth muscle, and there is evidence in animals that the major neurotransmitter of this system is vasoactive intestinal peptide (VIP). We have investigated the effect of VIP on bronchomotor tone and bronchial responsiveness to inhaled histamine in 6 atopic asthmatic subjects. The VIP was given by inhalation to avoid any indirect effects on the airways that might arise from the potent cardiovascular actions of this peptide when given systemically. The VIP (100 μg) was compared with control solution (diluent: 1% human serum albumin in 2 ml 0.9% saline) and with β₂-agonist (salbutamol, 200 μg) given double blind in random order on separate days. Specific airway conductance (SGaw) did not change after control or VIP inhalations, but it significantly increased after salbutamol inhalation. The provocation concentration of histamine causing a 35% fall in SGaw (PC₃₅) did not change after control inhalation, but significantly increased after VIP (from 2.18 ± 1.04 to 5.00 ± 2.31 mg/ml histamine, mean ± SE; p < 0.05), and after salbutamol (from 1.71 ± 0.83 to 15.6 ± 4.2 mg/ml, p < 0.01), the increase after salbutamol being significantly greater than after VIP. No changes in heart rate or blood pressure were found after any inhalation. We conclude that VIP protects against histamine-induced bronchoconstriction in human airways in vivo, and therefore has the capacity to be the neurotransmitter of nonadrenergic, noncholinergic inhibitory nerves in human airway smooth muscle.