A piglet model of acute respiratory failure was used to determine whether necrotizing tracheobronchitis (NTB) produced during high-frequency pneumatic flow interrupter (HFFI) ventilation could be attenuated by prior administration of 2 mg/kg hydrocortisone IV. Fourteen piglets (means age 3.6 days, means wt 1.4 kg) were anesthetized and paralyzed before saline lung lavage. The animals were randomly assigned to either placebo (P) or hydrocortisone (H) group. Continuous HFFI (10 Hz) was interrupted five times per minute by a 1-second deflationary pause. All animals were kept on 1.0 FI02 with ventilators adjusted to maintain adequate arterial blood gases. Airway pressures were similar for both groups. After 8 hours of ventilation the animals were sacrificed and their lungs inflated with formalin to 40 cm H2O. Sections were obtained from trachea, carina, main stem, and peripheral bronchi. A total airway injury (TAIS) was calculated by a pathologist unaware of treatment assignment. There was a significant difference (p less than 0.01, Wilcoxon rank sum) in TAIS scores between P (means 21.3) and H (means 7.8). In five out of seven P animals and in one out of seven H animals, NTB was severe and extended to the hilar bronchi. Although NTB is multifactorial in origin, the prior use of hydrocortisone may decrease the severity and extent of lesions by modifying the inflammatory response to this specific airway injury.