We anesthetized, paralyzed, and ventilated 32 dogs. In 16 dogs we measured total pulmonary resistance (RL) during inhalation of acetylcholine (ACh), serotonin (5-HT), and histamine (Hist) aerosols. Cooling both cervical vagi reduced the bronchoconstriction caused by 5-HT 64% (P = 0.001), reduced Hist-induced bronchoconstriction 17% (P = 0.003), and did not significantly reduce bronchoconstriction due to ACh. In seven dogs, we ventilated both lungs separately through a double-lumen catheter. Application of 5-HT to one lung increased the transpulmonary pressure amplitude in the homolateral but not in the contralateral lung. Cooling the homolateral vagus reduced this response 32% (P = 0.02). In nine dogs, we stimulated the peripheral ends of both cut cervical vagi before and during aerosol application of ACh, 5-HT, and Hist. ACh and Hist increased baseline RL 97 and 134%, respectively, without increasing the effect of vagal stimulation. 5-HT increased baseline RL only 27% but greatly augmented the effect of vagal stimulation (mean increase, 271%, P = 0.001). We conclude that 5-HT acts to potentiate vagal effects on airway smooth muscle via the efferent vagal pathway.