Controversy exists whether high frequency oscillatory ventilation with an active expiratory phase (HFO-A) should be used at low ventilator pressures or high alveolar volumes to minimize lung injury in the atelectasis-prone lung. We therefore ventilated 20 anesthetized, tracheostomized rabbits made surfactant-deficient by lung lavage in 1 of 3 ways: HFO-A at a high lung volume (HFO-A/HI), HFO-A at a low lung volume (HFO-A/LO), or conventional mechanical ventilation (CMV); all received 100% oxygen for 7 h. We examined oxygenation, lung mechanics, and lung pathology. Arterial oxygenation in the HFO-A/HI rabbits was kept greater than 350 mm Hg. Mean lung volume above FRC in these animals was 23.4 ml/kg. In rabbits ventilated with HFO-A/LO and CMV, arterial oxygen tensions were 70 to 100 mm Hg. Mean lung volumes were 7.8 and 4.3 ml/kg, respectively. Total respiratory system pressure-volume curves (P-V curves) showed no change from baseline in the HFO-A/HI group after 7 h of ventilation. The low lung volume groups (HFO-A/LO and CMV) showed a diminution in hysteresis of their P-V curves, lower total respiratory system compliance, more hyaline membranes and severe airway epithelial damage. (All changes significant with p less than 0.05). We conclude that maintenance of alveolar volume is a key mechanism in the prevention of lung injury during mechanical ventilation of the atelectasis-prone lung. For optimal outcome using high frequency oscillatory ventilation, alveoli must be actively reexpanded and then kept expanded using appropriate mean airway pressures.