Airway pressure release ventilation (APRV) shares several overlapping mechanisms with prone positioning in improving ventilation-perfusion mismatch in patients with acute respiratory distress syndrome (ARDS). However, the combination of APRV and prone positioning is seldom performed because assist/controlled ventilation remains the mainstay ventilatory mode. We describe 5 cases of severe ARDS where APRV and prone positioning were applied. All patients’ partial pressure of arterial oxygen (Pao2):inspired oxygen concentration (Fio2) ratios improved after treatment, and 3 patients were extubated within 72 hours of turning supine. In our experience, APRV can be safely used in the prone position in a select subgroup of ARDS patients with resulting significant oxygenation improvement.