Background: Evidence from European centres to support the use of nitric oxide (NO) in mature newborns with evidence of severe respiratory failure is sparse. Methods: Infants of >33 weeks’ gestation, <28 days old, and with severe respiratory failure requiring ventilatory support were randomised to receive or not to receive inhaled NO (iNO). The study was not blinded. Results: Sixty infants were recruited (29 allocated iNO, 31 no iNO) from 15 neonatal units in the UK, Finland, Belgium and the Republic of Ireland. 15/60 recruited babies died, and 8.1% of the survivors (4/45) were classified as severely disabled at 1 year. There was no statistically significant difference between the randomised groups in terms of the primary outcome of death or severe disability by the corrected age of 1 year (relative risk = 0.96 (95% confidence interval = 0.46–2.03); p = 0.86) (Fisher’s exact p = 1.00). The costs of NO were outweighed by reduced extra corporeal membrane oxygenation costs in the iNO group. The mean total hospitalisation costs were lower in the iNO group, although the mean difference (£1,697) was not statistically significant (95% confidence interval = –14,472 to 11,478). Conclusions: The results complement those of previous studies that suggest NO is cost-effective and reduces the need for extra corporeal membrane oxygenation in this group of babies. Overall survival rates compare unfavourably with results of US trials.