OBJECTIVE: Unusual clinical course. BACKGROUND: COVID-19 continues to place a tremendous burden on the healthcare system, with most deaths resulting from respiratory failure. Management strategies have varied, but the mortality rate for mechanically ventilated patients remains high. Conventional management with ARDSnet ventilation can improve outcomes but alternative and adjunct treatments continue to be explored. High-frequency oscillatory ventilation (HFOV), a modality now rarely used in adult critical care medicine, may offer an alternative treatment option by maximizing lung protection and limiting oxygen toxicity in critically ill patients failing conventional ventilator strategies. CASE REPORTS: We present 3 patients with severe acute respiratory distress syndrome (ARDS) and sepsis due to COVID-19 who all improved clinically after transitioning from conventional ventilation to HFOV. Two patients developed refractory hypoxemia with hemodynamic instability and multiple organ failure requiring vasopressor support and renal replacement therapy. After failing to improve with all available therapies, both patients stabilized and ultimately improved after being placed on HFOV. The third patient developed severe volutrauma/barotrauma despite extreme lung protection and ARDSnet ventilation. He showed improvement in oxygenation and signs of lung trauma slowly improved after initiating HFOV. All 3 patients were ultimately liberated from mechanical ventilation and discharged from the hospital to return to functional independence. CONCLUSIONS: Our experience suggests that HFOV offers advantages in the management of certain critically ill patients with ARDS due to COVID-19 pneumonia and might be considered in cases refractory to standard management strategies.