BACKGROUND Suprasystemic pulmonary hypertension (PH) is highly predictive of pulmonary morbidity and death in infants with congenital diaphragmatic hernia (CDH). OBJECTIVE To report the effects and tolerability of Prostaglandin E1 (PGE1) in newborns with severe CDH and life-threatening PH. METHODS Newborn infants with isolated CDH and life-threatening PH defined by an acute worsening of the cardiorespiratory function, and bidirectional or exclusive right-to-left shunting across the ductus arteriosus (DA) with an acceleration of the blood flow >1.5 m.s-1 assessed by Doppler echocardiography. Serial measurements of cardiorespiratory variables have been recorded before and after PGE1. RESULTS 18 infants (out of 102 in the cohort) were included in the study (gestational age: 39 ± 2 weeks). The median FiO2, and preductal and postductal SpO2 were 80% [50; 100], 91% [88; 95] and 86% [82; 91], respectively, before treatment. FiO2 decreased to 35% [30-40] (p = 0.001) at H6. Maximal blood flow velocities in the DA decreased after starting PGE1 from 2.2 m.s-1 [1.5-2.5] to 1 m.s-1 [0.55-1.2] (p < 0.001). CONCLUSIONS PGE1 treatment improved oxygenation and circulatory function in newborn infants with severe CDH and life-threatening PH. Our data provide evidence that restrictive DA may result in suprasystemic pulmonary hypertension in CDH infants, and that PGE1 may improve cardiorespiratory failure through reopening of the DA. METHODS Treatment study. METHODS Level III.