We conducted a multicenter, prospective, noncrossover, randomized study to determine whether high-frequency oscillatory ventilation (HFOV) would decrease the development or progression of air leak syndrome in infants with severe respiratory distress syndrome. Air leak syndrome was defined as pulmonary interstitial emphysema or gross air leak such as pneumothorax. Infants were eligible for study entry if they were less than 48 hours of age and had severe respiratory distress syndrome, defined by peak inspiratory pressure or the presence of air leak syndrome. Infants who weighed > or = 0.5 kg at birth were randomly assigned to receive either conventional ventilation (CV) or HFOV. HFOV was provided by a ventilator that operated at 15 Hz, with a 1:2 inspiratory/expiratory ratio and no background tidal breaths. Severity of pulmonary interstitial emphysema was scored independently by two neonatologists unaware of the infants' ventilatory group. Gross air leak severity was scored according to the number of chest tubes required and duration of air leak. Eighty-six infants received HFOV; 90 received CV. During the first 24 hours of the study, patients in the HFOV group received significantly higher mean airway pressure and lower inspired oxygen concentration, had significantly lower arterial carbon dioxide tension, and had a higher ratio of arterial to alveolar oxygen tension. When the HFOV and CV groups were compared with control for birth weight strata, study site, and inborn versus outborn status, HFOV significantly reduced the development of air leak syndrome in those patients who entered the study without the syndrome. We conclude that HFOV, when the strategy employed in this study is used, provides effective ventilation, improves oxygenation, and significantly reduces the development of air leak syndrome in infants with severe respiratory distress syndrome.