To compare high-frequency jet ventilation (HFJV) with pressure-limited time-cycled conventional ventilation (CV), we randomized 41 infants with clinical and radiographic evidence of respiratory distress syndrome during the first day of life to receive either HFJV or CV. Standardized ventilatory protocols were used for 48 hours, after which CV was administered to both groups. Despite comparable oxygenation (arterial/alveolar oxygen tension ratio), mean air-way pressure was lower in the HFJV group (9 ± 2 vs 13 ± 2 cm H2O, P <0.001), and thus the arterial/alveolar oxygen tension ratio corrected for mean airway pressure was improved in the HFJV group (P <0.05). PaCO2 was lower during HFJV (37 ± 3 vs 42 ± 3 mm Hg, P <0.05) despite a comparable peak inspiratory pressure. The incidence of air leaks, progression of intraventricular hemorrhage, and mortality during the 48-hour period did not differ between the two groups. Bronchoscoples in eight infants given HFJV and five given CV revealed no microscopic evidence of necrotizing tracheobronchitis, but one infant given HFJV had evidence of necrotizing tracheitis at autopsy. We conclude that for 48 hours during the acute stage of respiratory distress syndrome, HFJV can maintain adequate gas exchange at lower mean airway pressure than during CV, without an increase in the incidence of side effects. © 1987 The C. V. Mosby Company.