BACKGROUND: We have shown earlier that inhaled nitric oxide (iNO) administered by oxygen hood reduces pulmonary hypertension in an animal model (J Perinatol 2002; 22:50-6). Our objective in this study was to determine feasibility of iNO by oxygen hood in neonates with elevated alveolar-arterial oxygen gradients (A-aDO(2)). METHODS/PRINCIPAL FINDINGS: Masked randomized controlled pilot trial. Inclusion criteria were: gestation>or=34 weeks, age<7 days, with post-ductal arterial line, and A-aDO(2) 400-600. Infants were randomized to study gas (iNO 20 ppm or equivalent O(2) flow) for 1 hr which was then weaned over the next 4 hours. Primary outcome was PaO(2) one hour post-randomization. Four infants each were randomized to iNO or O(2) (controls). Two of the four infants given iNO had an increase in PaO(2) of >100 torr, while oxygenation was unchanged in the controls. Methemoglobinemia and other adverse effects were not noted in any infant. Environmental levels of NO and NO(2) were minimal (<1 ppm) at >0.3 m from the hood. CONCLUSIONS: Administration of iNO by oxygen hood is feasible. Larger randomized controlled trials are required to measure the efficacy and determine an appropriate target population for this technique. TRIAL REGISTRATION: ClinicalTrials.gov NCT00041548.