We examined an endogenous substance causing cough in awake guinea pigs. An intraperitoneal injection of phosphoramidon, a selective inhibitor of neutral endopeptidase (E.C. 126.96.36.199), caused cough in a dose-dependent fashion for approximately 40 min. At a dose of 3 × 10−3 mol/kg, phosphoramidon caused a total of 11.6 ± 1.4 coughs in 40 min. Phosphoramidon (3 × 10−3 mol/kg)-induced cough was significantly inhibited by systemic pretreatment with capsaicin (p < 0.01). Aerosols of FK 888 (1 min), a specific inhibitor of substance P (NK1 receptor, inhibited phosphoramidon (3 × 10−3 mol/kg)-induced cough in a dose-dependent fashion with complete inhibition at a dose of 10−5 M. Likewise, aerosols of FK 224 (10−5 M; 1 min), another inhibitor of NK1 and NK2 receptors, or lidocaine (4%, 1 min) significantly inhibited phosphoramidon (3 × 10−3 mol/kg)-induced cough (p < 0.01). Furthermore, aerosols of FK 888 (10−5 M; 1 min) significantly inhibited cough induced by cigarette smoke in awake guinea pigs (p < 0.01). These results suggest that substance P released from sensory nerves in the airway may be an endogenous substance causing cough and the substance P antagonist may be the drug for treatment of cough in respiratory disease.