Purpose: To compare the immediate and ultimate effects of an existing therapy (i.v. nitroprusside, SNP) with inhaled nitric oxide (iNO) in newborns with pulmonary hypertension (PPHN), at a center without ECMO, management often including surfactant and high-frequency oscillation.Hypothesis: a) iNO decreases risk of death or meeting ECMO criteria(the primary outcome) compared with SNP in infants with PPHN; b) iNO decreases A-a DO2 or OI within 0.5 hrs; and c) improved oxygenation is sustained at 6-12 hrs (secondary outcomes). Methods: Randomized, controlled, sequential trial, unblinded; crossover allowed. Guidelines for other medical therapy were used. Entry criteria included BW > 1500 g and significant PPHN(pre-defined diagnostic and A-aDO2 criteria). Excluded: infants with lethal congenital anomalies, profound lung hypoplasia, uncontrollable shock, or treated with nitrates in the prior 3 days. Standard definitions were used to evaluate responses to therapy; the protocol directed changes in iNO or SNP therapy; maximal doses were 48 ppm iNO and 5 μg/kg/min SNP. For study (not management) purposes, infants were classified as meeting ECMO criteria, per Short BL, Clin Perinatol 14:432, 1987. Results: The study was stopped after 3 years, due to decreasing enrollment and publication of related data. We enrolled 25 patients, 1 not treated (iNO arm); 16 received iNO and 12 SNP (4 crossed over). Major diagnoses were distributed equally between groups. Both groups had similar entry characteristics, with OI 40.9 ± 19.9(SD), A-aDO2 634 ± 18 torr. Nine (56%) iNO and 7 (58%) SNP treated infants met ECMO criteria or died; 5 died (3 in iNO group). Early responses in OI and/or A-aDO2 were noted in 13 (81%) of iNO and 3 (25%) of SNP recipients(p<0.01), and sustained responses in 9 (56%) and 2 (17%), respectively(p<0.05). Twelve babies were sent to an ECMO center: 6 (38%) of iNO and 9(75%) of SNP recipients (p<0.05); only 1 (crossover) infant received ECMO. No adverse events were noted, except for a temporary “rebound”in 2 patients, as iNO was discontinued. Conclusions: iNO did not decrease the risk of death or of meeting ECMO criteria compared with i.v. SNP, in infants with PPHN. However, iNO significantly improved immediate and sustained measures of oxygenation, and decreased the need for transport to an ECMO center.