In order to determine the response to high-frequency oscillatory ventilation (HFOV), used as an “early rescue” therapy, in a cohort of paediatric patients with acute respiratory distress syndrome (ARDS), a prospective clinical study was performed in a tertiary care paediatric intensive care unit. Ten consecutive patients, aged 12 days to 5 years with ARDS and hypoxaemic respiratory failure on conventional ventilation (CV), using a lung protective strategy, were managed with HFOV early in the course of the disease process (median length of CV 4 h). Arterial blood gases, oxygenation index (OI), alveolar-arterial oxygen difference (P(A-a)O2) and PaO2/FIO2 ratio were prospectively recorded prior to HFOV (0 h) and at predetermined intervals throughout the course of the HFOV protocol. There was a significant improvement in PaCO2 4 h after institution of HFOV ( P =0.012). A significant and sustained increase ( P <0.001) in PaO2/FIO2 ratio and a significant and sustained decrease ( P <0.001) in OI and P(A-a)O2 were demonstrated during the HFOV trial. These improvements were achieved 4 h after initiating HFOV ( P <0.05). Eight patients survived. There were no deaths from respiratory failure. Conclusion: In paediatric patients with acute respiratory distress syndrome and hypoxaemic respiratory failure on conventional ventilation, using a lung protective strategy, high-frequency oscillatory ventilation used as an “early rescue” therapy, improves gas exchange in a rapid and sustained fashion and provides a good outcome. Use of this therapy should probably be considered early in the course of the disease process.