Using a crossover study design, we compared a system of high-frequency jet ventilation with appropriate humidification to pressure-limited conventional ventilation in 12 preterm infants with a birth weight of 1.9 +/- 0.6 kg and gestational age of 32 +/- 2 weeks who had severe respiratory distress syndrome. After a control period of conventional ventilation, high-frequency jet ventilation was administered for 1 to 3 hours at a constant rate (250/min) and inspiratory to expiratory time (1:3 or 1:4) in the same fraction of inspired oxygen as during conventional ventilation. Average peak inspiratory pressure decreased from 29 +/- 3 cm H2O during conventional ventilation to 20 +/- 4 cm H2O during high-frequency jet ventilation (P less than 0.001), whereas positive end expiratory pressure was unchanged, resulting in a reduction in mean airway pressure from 14 +/- 3 to 10 +/- 2 cm H2O (P less than 0.001). There was a simultaneous decrease in PaCO2 (39 +/- 4 to 34 +/- 4 mm Hg, P less than 0.01), but PaO2 did not change. These data indicate that short-term high-frequency jet ventilation maintains gas exchange in infants with respiratory distress syndrome despite a lower PIP and Paw, and results in smaller airway pressure swings than during conventional ventilation. Thus, high-frequency jet ventilation may offer hope for reducing barotrauma in this population.