Abstract The effect of Nesosteine, a novel mucolytic agent, on natural host resistance mechanisms was investigated in different organs of mice and rats. Single or repeated administrations of nesosteine by the i.v. or oral route ( per os) were associated with significant increases in lung and spleen NK-mediated cytotoxicity, and in alveolar and peritoneal macrophages direct cytotoxocity. In both species the dose - response curve was bell-shaped, and optimal activity on both parameters seen at 1 mg/kg i.v. × 1, 100 mg/kg per os × 1 or 20 mg/kg per os × 5. Increases of at least 100% in lung NK and alveolar macrophages cytotoxicity were found in mice 48 h after single oral dosing at 100 mg/kg. The possible importance of Nesosteine immunostimulatory capacity in the activity of this compound in chronic hypersecretive bronchopulmonary disorders is discussed.