Twenty-five newborn infants with severe respiratory failure responding poorly to conventional mechanical ventilation were switched to high-frequency positive-pressure ventilation (HFPPV) at 90 to 180 cycle/min (mean 158), an estimated tidal volume less than or equal to 3 ml/kg body weight, an inspiratory time of 0.1 sec, and a PEEP of 3 to 17 cm H2O. In all infants, HFPPV increased Pao2(mean 66 torr) and decreased Paco2(mean 14 torr) within 1 h. Fourteen hours after onset of treatment, the Fio2requirement had decreased from 1.0 to 0.6 in all infants. Mean airway pressure (Paw) with HFPPV was usually less than or equal to Paw during conventional ventilation. In spite of the often high level of PEEP used, pneumothorax occurred in only 2 infants and bronchopulmonary dysplasia in 1. Eighteen (72%) infants survived and none died of respiratory failure. The use of HFPPV might be beneficial in neonates with severe respiratory failure that responds poorly to conventional therapy.