Twenty-eight newborn infants (birthweight, 2.4 +/- 1.1 kg; gestational age, 34.6 +/- 6.1 weeks) with respiratory distress syndrome (RDS), meconium aspiration syndrome, or pneumonia who deteriorated in spite of optimal conventional mechanical ventilation (CMV) and exogenous surfactant therapy were treated with high-frequency jet ventilation (HFJV) and continued surfactant therapy. For enrollment, infants had to have a limited response to surfactant therapy and conventional ventilation, and meet clinical criteria that confirmed clinical deterioration and severity of illness. Study infants had received exogenous calf lung surfactant extract (CLSE) and conventional ventilation prior to the start of HFJV at 46.3 +/- 8.2 hours of age. Patients initially responded to HFJV alone with significant improvement in several respiratory variables, but deteriorated subsequently and receive additional doses of exogenous surfactant on HFJV. Exogenous surfactant and HFJV resulted in significant and sustained improvement in several respiratory variables. Only ten patients deteriorated to meet criteria for a second surfactant dose on HFJV, and two patients received a third dose. Twenty-five of the 28 patients studied survived (89%). No patients received extracorporeal membrane oxygenation or were discharged home on oxygen. The results of this pilot study suggest that the combination of HFJV and exogenous surfactant replacement may be effective in treating infants with more severe respiratory failure, and indicate the need for more extensive controlled investigations.