Chronic hypoxia produces pulmonary artery hypertension and remodeling of pulmonary arteries with hypertrophy of smooth muscle in the media and extension of smooth muscle into more distal small precapillary arteries. The present study investigated the influence of heparin, an inhibitor of platelet-derived growth factor, and of the clotting cascade on this remodeling. Mice maintained in room air or 10% O₂ for 26 days were treated with low-dose heparin at 75 units/kg or high dose heparin at 300 units/kg. Pulmonary hypertension and right ventricular hypertrophy developed in the hypoxic mice compared with the room air mice as evidenced by the greater (p < 0.05) right ventricular systolic pressure (36 ± 4 SEM versus 21 ± 1 mmHg) and the increase (p < 0.05) in right heart weight/left ventricular plus septal weight (35 ±1.6 SEM versus 25.2 ± 1.3). Hypoxia also induced smooth muscle hypertrophy in small pulmonary arteries, with an increase (p < 0.05) in the percent media thickness/vascular diameter from 5.7 ± 1 SEM to 13.3 ± 3 and an apparent decrease (p < 0.05) in distal small pulmonary arteries from 4.4 ± 0.2 SEM to 2.05 ± 0.1 per 100 alveoli. High-dose heparin partially but significantly (p < 0.05) prevented the pulmonary artery hypertension (right ventricular systolic pressure of 28 ± 2 mmHg), the right ventricular hypertrophy (right ventricular weight/left ventricular plus septal weight of 30.1 ± 1) and remodeling of distal small pulmonary arteries (media thickness/vascular diameter of 8.4 ± 1%, small pulmonary artery/100 alveoli of 3.63 ± 0.1). Low-dose heparin, which did not alter clotting as measured by an activated partial thromboplastin time, tended to prevent pulmonary artery hypertension and remodeling but less consistently. Heparin can thus substantially inhibit pulmonary artery hypertension and remodeling in chronically hypoxic mice. The mechanism of heparin interference is unknown.