The use of continuous negative pressure was prospectively studied in 30 preterm and term hypoxemic (PaO2 < 45 mm Hg) neonates. Infants were randomly assigned to either positive end-expiratory pressure or continuous negative pressure if conventional positive pressure ventilation failed to improve oxygenation. Crossover to the alternative therapy occurred if infants remained hypoxemic after 2 hours. In the continuous negative pressure group, 2 (13%) crossed over to positive end-expiratory pressure, whereas 11 (73%) in the positive end-expiratory pressure group crossed over to continuous negative pressure (p = 0.003). Only five patients remained in the positive end-expiratory pressure group 36 hours after randomization. Compared with positive end-expiratory pressure, continuous negative pressure significantly increased PaO2 (69 +/- 17 mm Hg vs 36 +/- 8 mm Hg) and arterial-alveolar ratio (0.098 +/- 0.070 vs 0.057 +/- 0.014) 30 minutes after randomization and after crossover to continuous negative pressure (60 +/- 12 mm Hg vs 37 +/- 5 mm Hg, and 0.154 +/- 0.096 vs 0.058 +/- 0.009). The use of continuous negative pressure did not increase morbidity. Overall survival was 83.3%. Only three infants were referred to extracorporeal membrane oxygenation. Rescue therapy with continuous negative pressure is effective in infants with refractory hypoxemia and may be considered before referral for extracorporeal membrane oxygenation.