We retrospectively reviewed data on high frequency oscillatory ventilation (HFOV) settings and pulmonary function in 14 extremely low birth weight infants who were treated with piston-type HFOV immediately after birth for severe respiratory distress to investigate the cause of pulmonary interstitial emphysema (PIE) associated with HFOV. PIE developed a mean of 23 hr after the initiation of HFOV in 6 infants. Eight infants did not develop PIE and served as the control group. The lowest mean airway pressure (MAP) in the PIE group, which occurred immediately before disease onset was 5.2 cm H2O. The lowest MAP in the control group was 7.5 cm H2O (p < 0.01), which occurred immediately before the ventilatory mode was changed from HFOV to conventional mechanical ventilation for weaning from mechanical ventilation. Respiratory system compliance (Crs) 12 hr after birth was below normal in both groups and there was no significant difference between groups. These results suggest that an unusually low MAP may contribute to PIE during piston-type HFOV in the presence of low Crs. It is therefore important to maintain a high MAP during HFOV until pulmonary compliance becomes normal.