The effects of 24 h of high-frequency oscillatory ventilation (HFOV) applied to premature primates with hyaline membrane disease (HMD) were assessed by serial gas exchange and in vivo lung distensibility measurements, and by postmortem lung phospholipid analysis. Results in 7 animals with HMD treated with HFOV were compared with those in 6 animals with HMD treated with conventional mechanical ventilation. No differences in arterial to inspired PO2 ratios, total lung capacity, airway lavage, or lung homogenate phospholipid or disaturated phosphatidylcholine were found between the 2 groups. Arterial PCO2 was lower in the HMD-HFOV group at 6 and at 12 h. There was no difference in lung dry to wet weight ratios; the ratio in both groups of HMD animals was less than that for premature primates without HMD. We conclude that HFOV is useful in maintaining adequate CO2 elimination but does not improve arterial oxygenation or alter the natural history of experimental HMD.