To assess the role of high-frequency ventilator strategy in the propagation of airway injury, we compared the tracheobronchial histologic alterations in 20 newborn piglets ventilated for 8 hours with high-frequency flow interruption (HFFI). Ten animals were assigned to HFFI with a strategy of continuous pulsations at a frequency of 10 Hz and a mean airway pressure of 16 cm H2O. Ten piglets were treated at identical settings except for 10 one-second baseline pauses per minute to a positive end-expiratory pressure of 5 cm H2O. A semiquantitative scoring system was used to grade light microscopic tissue alterations in the trachea, carina, and mainstem bronchi. Ultrastructural changes were evaluated with scanning electron microscopy. The HFFI-continuous-treated piglets had significantly more damage in all areas than the HFFI-baseline pause group (P less than .001). The upper tracheas of animals in both groups were altered to a greater extent than the lower tracheas (P less than .007). In addition, numerous "skip" areas of injury were noted throughout the tracheas. High-frequency ventilator strategy is a determinant of the severity of airway histologic changes. Factors that adversely affect tissue oxygenation or cause direct mechanical trauma may also influence the degree of injury. Optimal operating characteristics and limitations of different high-frequency devices must be assessed before their use in human neonates.