1. Studies were designed to investigate the responses of isolated pulmonary arteries from control pigs or pigs chronically treated with dexfenfluramine (7.2 mg/kg per day orally for 4 weeks). 2. Rings with and without endothelium were suspended in organ chambers for recording of isometric tension. 3. Dexfenfluramine (10[-9] to 10[-6] M) did not affect vascular tone, but at higher concentrations caused contractions that were not affected by indomethacin, methiothepin, the presence of endothelium or by the chronic treatment. 4. Chronic treatment augmented the endothelium-dependent relaxations to serotonin and aggregating platelets but not those to adenosine diphosphate. It did not affect the contraction or rings without endothelium evoked by platelets, nor the relaxation to SIN-1, a nitric oxide donor. The maximal contraction to endothelin-1 (but not that of norepinephrine) was impaired in treated pigs. 5. These results show that dexfenfluramine causes contraction of isolated porcine pulmonary arteries only at concentrations higher than 3 x 10(-6) M, and that chronic treatment with dexfenfluramine potentiates the endothelium-dependent relaxations to serotonin and aggregating platelets in the porcine pulmonary artery without affecting their direct effect on the smooth muscle.