The anorexiant dexfenfluramine, which inhibits 5-hydroxytryptamine (5-HT) uptake, has been associated with an increase in the relative risk of developing primary pulmonary hypertension. The aim of this study was to investigate in rats whether dexfenfluramine (1) alters the pulmonary vasomotor effects of 5-HT and (2) aggravates the development of pulmonary hypertension during exposure to various levels of chronic hypoxia. In isolated lungs from normoxic rats, dexfenfluramine up to 10-4 M did not elicit any vasoactive effects, and neither did pretreatment with dexfenfluramine (10-5 M in the perfusate) modify the vasoactive effects of 5-HT. In normoxic conscious rats, dexfenfluramine given intravenously potentiated the pulmonary pressor response to acute hypoxia (10% O2). In rats chronically treated with dexfenfluramine during a 2-wk exposure to 15% or 10% O2, plasma 5-HT concentrations were significantly increased compared with hypoxic controls, whereas no differences were found for pulmonary artery pressure, right ventricular hypertrophy, or pulmonary vessel muscularization. In contrast, a continuous 5-HT infusion providing a sustained increase in plasma 5-HT levels was associated with increased muscularization of distal pulmonary arteries in response to 10% O2. Simultaneous administration of dexfenfluramine prevented the effect of exogenous 5-HT on vascular remodeling. Our findings show that dexfenfluramine does not potentiate the development of pulmonary hypertension in rats exposed to chronic hypoxia, despite its effect on plasma 5-HT concentrations.