Abstract High-risk infants with a fetal pattern of circulation demonstrate hyperactivity of the pulmonary vascular bed in response to stimuli including mucous plugging, atelectasis, and endotrachial tube suctioning. The resultant increase in pulmonary vascular resistance (PVR) leads to pulmonary hypertension, severe right-to-left shunting, and hypoxemia. Stimuli that trigger pulmonary hypertension cause hypoxia, suggesting the importance of hypoxic pulmonary vasoconstriction (HPV). Although many humoral mediators of HPV have been hypothesized, none have been proven. This study investigates the possible role of the cyclo-oxygenase derivatives thromboxane A 2 and prostacyclin as determinants of hypoxic pulmonary hypertension. Open-chested lambs were ventilated with 13% O 2 prior to and following treatment with OKY 046, a selective thromboxane inhibitor. In untreated lambs, the partial pressure of arterial oxygen fell from 80 ± 27 (x̄ ± SD) to 35 ± 13 mm HG ( P < .01). The mean arterial pressure (MAP) remained at 50 ± 7 mm HG, and the cardiac output (CO) was unchanged at 0.8 ± 0.2 L/min. The mean pulmonary arterial pressure (MPAP) rose from 11 ± 4 to 20 ± 4 mm HG ( P < .01) whereas the PVR increased 70% ( P < .01). TxB 2 rose from 147 ± 85 to 271 ± 154 pg/mL ( P < .05), and 6-keto-PGF 1α rose from 105 ± 96 to 142 ± 110 pg/mL. These substances are the hydrolysis products of TxA 2 and prostacyclin respectively. In animals treated with OKY 046 prior to ventilation with 13% O 2, values for MAP, CO, and PVR were similar to those of the nontreatment period. However, there was no significant rise in either MAP or PVR. Following treatment with OKY 046, TxB 2 levels fell from 125 ± 82 to 68 ± 54 pg/mL ( P < .05), and 6-keto-PGF 1α levels rose from 306 ± 164 to 373 ± 125 pg/mL ( P < .05). These results support the thesis that cyclo-oxygenase derivatives TxA 2 and prostacyclin are mediators of HPV.