Inhaled nitric oxide is used to alleviate pulmonary hypertension and hypoxaemia, but generates toxic free radicals and oxides of nitrogen (NO(x)), which can cause rebound-hypoxia and additional pulmonary and other morbidity. To address these problems, we assessed the efficacy of inhaled O-nitrosoethanol gas (ENO) as a novel alternative means of providing nitric oxide bioactivity in the treatment of persistent pulmonary hypertension of newborns. We administered ENO over 4 h to seven neonates who required assisted ventilation, and who had an oxygenation index of 25 or more. ENO was then shut off for 15 min before start of treatment with inhaled nitric oxide. Our results show that ENO produced sustained improvements in postductal arterial oxygenation and systemic haemodynamics, which were maintained during the off-drug observation period. Increases in methaemoglobinaemia were modest and toxic NO(x) were not detected. Thus, ENO can improve oxygenation and systemic haemodynamics in neonates, and seems to reduce rebound hypoxaemia and production of toxic byproducts.