A 47-year-old white woman, with Cowden syndrome diagnosed at 40 years of age and an exposure to the appetite suppressant dexfenfluramine for 1 year in 1989, was referred to the French Reference Center for Severe Pulmonary Hypertension with a 6-month history of progressive dyspnea (New York Heart Association functional class III). The main clinical manifestations of Cowden syndrome were multiple cutaneous lesions, renal cysts, tracheal papilloma, breast papilloma, uterine fibroids, dental abnormalities, thyroid nodules, and macrocephaly. At diagnosis of PAH, the 6-min walk distance was 307 m. Right-sided heart catheterization confirmed precapillary pulmonary hypertension, with mean pulmonary artery pressure of 49 mm Hg, pulmonary capillary wedge pressure of 8 mm Hg, right atrial pressure of 9 mm Hg, cardiac index of 4.6 L/min/m2, pulmonary vascular resistance of 367 dyne/s/cm5, and no acute vasodilator response to nitric oxide. Usual screening for other causes of pulmonary hypertension was negative. PAH was related to anorexigen exposure, and the patient received the oral dual endothelin receptor antagonist bosentan in association with diuretics and oral anticoagulants. Four months later, she stabilized in New York Heart Association functional class III, and there was no change in 6-min walk distance. Repeated right-sided heart catheterization showed no change in pulmonary hemodynamics (mean pulmonary artery pressure of 43 mm Hg, cardiac index of 3.9 L/min/m2, and pulmonary vascular resistance of 392 dyne/s/cm5).