Airway pressure release ventilation (APRV) delivers continuous positive airway pressure (CPAP) and may support ventilation simultaneously. This investigation tested whether, after acute lung injury (ALI), APRV promotes alveolar ventilation and arterial oxygenation without increasing airway pressure (Paw) above the CPAP level and without depressing cardiac function. Ten anesthetized dogs randomly received either intermittent positive-pressure ventilation (IPPV) or APRV. APRV was delivered with a continuous-flow CPAP system. Expiration occurred when a switch in the expiratory limb opened and Paw decreased to near-ambient, which decreased lung volume. After baseline data collection, ALI was induced by infusing oleic acid iv. Two hours later, IPPV and APRV were administered randomly, and data were collected. With normal lungs, APRV and IPPV achieved similar gas exchange and hemodynamic function. During ALI, arterial oxygenation was improved, and peak Paw which did not exceed the CPAP level, was lower during APRV. Similar minute ventilations were delivered by both modes but resulted in lower PaCO2 with APRV. Thus, APRV decreased physiologic deadspace ventilation. Hemodynamic status was similar during both modes. Therefore, APRV is an improved method of oxygenation and ventilatory support for patients with ALI that will allow unrestricted spontaneous ventilation and may decrease the incidence of barotrauma.