At birth, pulmonary blood flow increases dramatically. In some children, PPHN occurs, resulting severe hypoxemia. Reports indicate that inhalational nitric oxide (INO) causes selective pulmonary vasodilation, increases arterial oxygen tension and may decrease the use of ECMO in PPHN. However, the optimal dose and timing of INO administration in PPHN remains unclear. We hypothesized that in PPHN (i) NO at 2 ppm is effective at acutely increasing oxygenation as measured by oxygenation index (OI); (ii) Early use of 2 ppm NO is more effective than control (0 ppm) in preventing clinical deterioration; and (iii) NO at 20 ppm is effective at acutely decreasing OI in infants with OI >35. To test these hypotheses, we initiated a randomized, controlled trial of inhalational NO in 3 nurseries in a single metropolitan area. 26 children, gestational age of 37.3 weeks and average age less than 1.5 days were enrolled. 23 of 26 infants had echocardiographic evidence of pulmonary hypertension. Upon enrollment, average OI in the control group, NO at 0 parts per million (ppm) (n=13) was 41.5±3, compared to 42.9±2 in the 2 ppm NO (n=13) group (p=NS). Treatment with NO at 2 ppm for an average of 52 minutes was associated with a decrease in OI to 33.4±3. 11 of 13 (85%) control patients and 12 of 13 (92%) of the low dose NO group demonstrated clinical deterioration and were treated with NO at 20 ppm. In the control group, treatment with NO at 20 ppm decreased OI from 50±2 to 40±2, whereas in the 2 ppm NO group with a change in NO concentration from 2 to 20 ppm OI did not change. Interestingly, 6 of 12 patients in the low dose NO group required ECMO, compared to 1 of 11 in the control group. We conclude that in infants with PPHN inhalational NO at 2ppm can acutely improve oxygenation, but does not prevent clinical deterioration. We speculate that initial treatment with 2 ppm NO may attenuate the clinical response to 20 ppm NO.