The mucolytic activity of azelastine, an antiallergic/antiasthmatic drug, in mice and rats was investigated. The oral administration of test compounds 30 min before phenol red i.p. injection stimulated dye secretion in the trachea of mice. The resulting oral ED50's (mg/kg) were: azelastine, 0.16; salbutamol, 2.5; N-acetylcysteine, 61.8; S-Carboxymethyl-l-cysteine, < 100; bromhexine, > 100; and potassium iodide, approximately 200. In rats, several drugs stimulated secretion of fluorescein sodium (FINa) in the tracheobronchial lumen. The resulting oral ED50's (mg/kg) were: azelastine, 0.33; terbutaline, 0.3; salbutamol, 0.89; and S-carboxymethyl-l-cysteine, 56.8. Terfenadine and diphenhydramine (1-10 mg/kg, p.o.) did not stimulate tracheal secretion in rats and mice. The mucolytic activity of azelastine may contribute to its overall effectiveness, including antitussive activity in asthmatics. Finally, this activity seems to be dissociated from its H1-histamine receptor blocking activity.