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-aDO2). Methods/Principal Findings: Masked randomized controlled pilot trial. Inclusion criteria were: gestation≥34 weeks, age, <7 days, with post-ductal arterial line, and A-aDO2 400-600. Infants were randomized to study gas (iNO 20 ppm or equivalent O2 flow) for 1 hr which was then weaned over the next 4 hours. Primary outcome was PaO2 one hour postrandomization. Four infants each were randomized to iNO or O2 (controls). Two of the four infants given iNO had an increase in PaO2 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 NO2 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. © 2009 Ambalavanan et al.