INTRODUCTION Because of the high mortality, potential limitations, and inherent adverse effects associated with conventional therapies, as well as extracorporeal membrane oxygenation, for persistent pulmonary hypertension of the newborn (PPHN), alternative modes of ventilatory support have been researched. There is anecdotal evidence that high-frequency flow interruption ventilation (HFFI) benefits neonates with severe air leak and lung diseases unresponsive to conventional ventilation, so we conducted a study to compare the hospital course, survival rate, and incidence of chronic lung disease of neonates with PPHN treated with hyperventilation (HV) and HFFI. METHODS Enrolled in the study were 36 neonates who (1) were treated with HV and a fraction of inspired oxygen of 1.0 for PPHN, (2) had arterial partial pressure of oxygen (P(aO2)) values <or= 60 mm Hg, and (3) met the inclusion criteria. Neonates were assigned to either HV or HFFI treatment and there were 18 neonates in each treatment group. RESULTS HFFI did not statistically increase survival (78% vs 44%, p = 0.087). Compared to the HV group, the HFFI group had: (1) fewer neonates requiring vasopressor support (7 vs 14, p = 0.042); (2) lower mean pH (7.37 vs 7.52, p < 0.001) and higher mean P(aCO2) (37.7 vs 22.1 mm Hg, p < 0.001) for neonates with P(aO2) >or= 120 mm Hg; (3) shorter mean time to P(aO2) >or= 120 mm Hg (13.5 vs 50.2 h, p = 0.001); (4) shorter mean time to reduced fraction of inspired oxygen (16 vs 84 h, p < 0.001); (5) shorter mean time to fraction of inspired oxygen 0.70 (53 vs 187 h, p < 0.001); (6) shorter mean time to extubation (8.1 vs 18.7 d, p = 0.033); (7) shorter length of hospitalization (22.7 vs 50.6 d, p = 0.025); and (8) fewer neonates with chronic lung disease (1 vs 5, p = 0.018). CONCLUSIONS HFFI with the ventilation strategy we describe accomplishes sustained hyperoxygenation without hypocarbia and alkalosis, and response to HFFI can predict outcomes. HFFI does not significantly reduce mortality, but it does reduce the length of mechanical ventilation, the length of hospitalization, and the incidence of chronic lung disease in neonates with PPHN. The nonrandomized design of our study precludes firm conclusions about the potential benefits of HFFI. The results may be biased by practice variations. Additional randomized controlled trials are warranted to determine the efficacy of HFFI in neonates with PPHN.