Short-term exposure to cigarette smoke is known to accelerate mucociliary (m.c.) activity in the rabbit maxillary sinus and to increase m.c. clearance from the lung. Several components of cigarette smoke stimulate sensory C-fibre endings in the airways. Some of these fibres contain the neuropeptide substance P (SP), and release of SP after stimulation of C-fibre endings is thought to accelerate m.c. activity. The purpose of the present investigation was to study possible mechanisms responsible for the increase of m.c. activity in the rabbit maxillary sinus after exposure to cigarette smoke. When delivered once a minute, 2.5 ml smoke puffs each accelerated the m.c. activity, the maximal increase being 34.7 +/- 2.4%, with a latency of 3.7 +/- 0.5 s. The response to cigarette smoke was suppressed in rabbits pretreated with atropine, an SP antagonist [(D-Pro2, D-Trp7,9)SP], capsaicin or hexamethonium. A response, albeit reduced, elicited in atropinized rabbits indicated a non-cholinergic component. The atropine-resistant acceleration was abolished by the SP antagonist. Together the results suggest that cigarette smoke accelerates m.c. activity through a reflex involving sensory SP containing C-fibres (afferent pathway) and cholinergic (probably parasympathetic) effector neurones (efferent pathway). Hence, the effect of cigarette smoke on the m.c. system reflects the joint release of both SP and acetylcholine. This dual mechanism may be of importance in the regulation of m.c. activity.