To determine if high-frequency jet ventilation is beneficial in neonates with persistent pulmonary hypertension, we compared the ventilator settings, blood gas concentrations, and outcome of infants who met established criteria for a high predictive mortality. During a six-year period, 14 neonates who had severe respiratory failure and hypoxemia while receiving conventional ventilation were treated with high-frequency jet ventilation. Twenty-three comparable infants meeting the same criteria were treated exclusively with conventional ventilation. After initiation of high-frequency jet ventilation there was a significant reduction in mean airway pressure and partial pressure of arterial carbon dioxide (PaCO2). In contrast, neonates treated exclusively with conventional ventilation continued to have higher airway pressures and PaCO2. However, there was no difference in the alveolar-to-arterial oxygen gradient, air leakage, incidence of bronchopulmonary dysplasia, or duration of assisted ventilation or oxygen supplementation. Furthermore, mortality was comparable in both groups of infants. These preliminary observations suggest that high-frequency jet ventilation can reduce airway pressure and PaCO2 in neonates with persistent pulmonary hypertension but does not appear to improve outcome.