Severe acute chest syndrome afflicts patients with sickle cell disease and can cause hypoxemia refractory to conventional treatments. Obstructive mucus plugging and the development of acute respiratory distress syndrome may underlie the pathophysiology of refractory hypoxemia in acute chest syndrome. Although high-frequency oscillatory ventilation (HFOV) is well established in the treatment of pediatric acute respiratory distress syndrome, there is no support in the literature for its role in managing hypoxemia in acute chest syndrome. In disease processes with high airways resistance and obstructive mucus plugging, HFOV may predispose to air-trapping and increased morbidity secondary to air leak syndromes. We report the first successful HFOV management of pediatric patients suffering from severe acute chest syndrome and hypoxic respiratory failure. These cases suggest that HFOV should be strongly considered for patients with severe acute chest syndrome that is refractory to conventional mechanical ventilation.