High-frequency ventilation (HFV) and inhaled nitric oxide (iNO) represent two treatment options in hypoxemic respiratory failure of neonates and infants. We report the case of a former 28weeks of gestation premature infant with bronchopulmonary dysplasia (BPD) who suffered from severe hypoxemia secondary to respiratory syncytial virus (RSV) pneumonia at the age of seven months. Following initial deterioration during spontaneous breathing, intubation and conventional mechanical ventilation (CMV) with peak inspiratory pressures up to 40 mbar at an FiO2 of 1.0 were required. Sonographically only a minor pressure gradient was demonstrated across the pulmonary valve as shown by tricuspid regurgitation. At an oxygenation index(OI) of 20 we started treatment with iNO in order to improve VQ-mismatching and improve oxygenation. However no increase of arterial oxygenation was noted. Following termination of NO inhalation the mode of ventilation was switched to HFV with mean airway pressures of up to 20 mbar. Again oxygenation was unaffected with an OI still at 20. At that stage a second trial of iNO was commenced starting at a concentration of 20 ppm. Within minutes oxygenation improved significantly, the OI was calculated at 7 only ten minutes after the start of NO inhalation. This effect on oxygenation was sustained for the duration of several days during high-frequency ventilation until gradual weaning from iNO could be performed. We conclude that adequate lung expansion is required in order to achieve the maximum benefit from iNO therapy. This appears to be more readily achieved by the use of HFV as compared to CMV. In cases of RSV pneumonia in infants at high risk (BPD infants, post cardiac surgery infants, immunosuppressed infants) this therapeutic regimen should be considered, particularily if these therapies (HFV, iNO) have proved inefficient used as single treatment modalities.