Upper respiratory tract virus infections may enhance airway responsiveness to histamine in normal subjects. We have studied the effects of parainfluenza Type I (Sendai) virus infection of the upper respiratory tract on the airway responsiveness to acetylcholine (ACh) and substance P administered by either the inhaled or intravenous route in the anesthetized guinea pig. Airway responses to electrical stimulation of the vagus nerves in the presence of atropine (1 mg.kg-1 i.v.) were also studied. After four to five days following virus infection, mean pulmonary insufflation pressure increased significantly in response to inhaled ACh compared to that in control animals. Responses to intravenous ACh were not enhanced. By contrast, responses to both intravenous and inhaled substance P were increased. In addition, mean pulmonary insufflation pressure after electrical stimulation of the vagus nerves for 30 seconds at 5 V, 5 msec (frequencies of 3, 10, and 30 Hz) were all enhanced after virus infection. We conclude that the increased airway responsiveness observed to the exogenous administration of the neurotransmitters ACh and substance P after viral respiratory infection may be due to different mechanisms possibly associated with an interference with the epithelium.