We determined whether closing the ductus arteriosus of the fetal lamb several d before birth would cause persistent pulmonary hypertension after birth. Six experimental fetuses who had their ductus arteriosus ligated 3-17 d before delivery, three control fetuses who had sham ligation of the ductus arteriosus 14 d before delivery, and six control fetuses who had no prenatal surgery were delivered by cesarean section between 138 and 144 d of gestation. Each was instrumented to measure pulmonary and systemic arterial pressures and pulmonary blood flow. Each newborn lamb was ventilated with room air during the first 45 min after birth and then with decreasing amounts of inspired oxygen from 100 to 9%. Pulmonary arterial pressure decreased significantly when ventilation was begun in the control lambs but not in the lambs who had their ductus arteriosus ligated before delivery. Throughout the experiment, pulmonary arterial pressure and total pulmonary resistance were significantly higher, and pulmonary blood flow was significantly lower in the lambs who had their ductus arteriosus ligated before delivery. In two of them, pulmonary arterial pressure was greater than or equal to systemic arterial pressure, even during ventilation with 100% oxygen. This animal preparation provides a method of investigating persistent pulmonary hypertension in the newborn lamb and may provide insight into an etiology of the syndrome of persistent pulmonary hypertension of the newborn.