To investigate the mechanism of the cough-like reflex (CLR), we employed 1.1-dimethyl-4-phenylpiperazinium iodide (DMPP). In dogs anesthetized with alpha-chloralose, CLR was induced by administration of DMPP (i.v. and intracarotid arterial), lobeline and nicotine. Repeated administration of DMPP did not cause a tachphylaxis, however, lobeline and nicotine did induce a tachphylaxis. DMPP (i.a.), lobeline, nicotine and histamine caused an increase in respiratory resistance as measured by a Respiratory Resistance Meter, while DMPP (i.v.) did not. The ED50 of morphine, codeine, oxymethebanol, picoperidamine and piclobetol on CLR with DMPP was higher than that of those drugs employed for the peripherally-induced cough. CLR with DMPP was not affected by isoproterenol, ephedrine, atropine and propranolol. CLR was markedly depressed by hexamethonium and slightly depressed by benzonate. CLR was abolished after bilateral vagotomy or bilateral denervation of the carotid sinus nerves. These results indicate that the mechanism of CLR with DMPP is different from that of peripherally-induced cough and the carotid body chemoreceptor plays an important role in CLR with DMPP. This CLR may be useful for demonstrating the site of action and the mechanism of antitussive drugs.