Dexfenfluramine has been shown to reduce body weight and lower blood pressure in obese individuals. However. it is not clear whether the blood pressure-lowering effect is due to dexfenfluramine or to the loss of weight. This project was designed to study the effect of a 5-d treatment of dexfenfluramine on blood pressure changes in obese postmenopausal women. Twenty women aged 51-60 y matched for body mass index [BMI (in kg/m2) of 34.5-50.1] were assigned to either the dexfenfluramine group (15 mg orally twice a day for 5 d) or the control group. All subjects were instructed about an isoenergetic diet. Twenty-four-hour ambulatory blood pressure, plasma catecholamines, glucose, insulin, and lipids were measured at the beginning and repeated at the conclusion of the study. On day 5 the mean systolic (SBP) and mean diastolic blood pressures (DBP) in the dexfenfluramine group were lower than those of the control group (SBP: 114+/-7 mm Hg in the dexfenfluramine group compared with 124+/-12 mm Hg in the control group, P < 0.05; DBP: 70+/-9 mm Hg in the dexfenfluramine group compared with 76+/-10 mm Hg in the control group, P < 0.05). The mean plasma norepinephrine concentration was lower in the dexfenfluramine group than in the control group (1.60+/-0.5 compared with 2.41+/-0.5 nmol/L, respectively, P < 0.05). No differences were noted in epinephrine, glucose, insulin. and lipid concentrations between the two groups. We showed that a 5-d treatment of dexfenfluramine decreases blood pressure and reduces heart rate in obese postmenopausal women. Our data suggest that these effects are results of the direct action of dexfenfluramine.