In critically ill nearly full-term newborns with persistent pulmonary hypertension (PPHN), iNO has been shown to improve the oxygenation, thereby reducing the use of extracorporeal membrane oxygenation (ECMO). Whether iNO is also beneficial at an earlier stage of respiratory failure, and in preterm infants remains unknown. Thus, we undertook a randomized clinical trial in 25 French and 8 Belgium centers. The inclusion criteria were: newborns <7 days of age, with oxygenation index (OI) 12.5-30 (≤32 wks) or 15-40 (≥33 wks), despite optimized therapy including surfactant. The primary endpoint was a decrease in OI at 2hrs of therapy, and the secondary ones: use of alternate therapy beyond 2hrs, avoidance of ECMO, and survival without bronchopulmonary dysplasia (BPD). After informed consent, 189 newborns were randomized between 10 ppm iNO (n=92) and control therapy (n=97) according to the underlying disease: hyaline membrane disease (n=123), 'idiopathic' PPHN (n=33), or meconium aspiration syndrome (n=33), the type of ventilation: conventional mechanical (n=67) or high-frequency oscillatory ventilation (n=122), and the gestational age: ≤32 (n=83) or μ33 wks (n=106). The decrease in OI was greater in the iNO than in the control group at 2hrs (median -6.5 vs-4.5, P=.057). Beyond 2 hrs, 37 control infants received iNO, and 13 others surfactant therapy as compared to only 7 in the iNO group. No patient but one justified ECMO. While a trend in lower intracranial hemorrhages (21vs 27), leukomalacia (4 vs 10), and deaths (15vs 20) was observed in the iNO group, significantly less either iv (23 vs 33) or inhaled (2 vs 8)(P<.05) steroids were used, suggesting less severe BPD. Shorter median duration of ventilation (7±7 vs 8±10 days[IQR], P=.047) and of stay in the ICU (11±18 vs 16±17 days [IQR], P=.055) was likewise observed. Thus, iNO does not increase neurological morbidity in preterm newborns. When introduced at an earlier stage of the respiratory disease, iNO may significantly reduce the respiratory morbidity, and shorten the stay in the ICU.