IMPORTANCE: Up to 25% of patients with normal lungs develop acute lung injury (ALI) secondary to mechanical ventilation, with 60% to 80% progressing to acute respiratory distress syndrome (ARDS). Once established, ARDS is treated with mechanical ventilation that can paradoxically elevate mortality. A ventilation strategy that reduces the incidence of ARDS could change the clinical paradigm from treatment to prevention. OBJECTIVES: To demonstrate that (1) mechanical ventilation with tidal volume (VT) and positive end-expiratory pressure (PEEP) settings used routinely on surgery patients causes ALI/ARDS in normal rats and (2) preemptive application of airway pressure release ventilation (APRV) blocks drivers of lung injury (ie, surfactant deactivation and alveolar edema) and prevents ARDS. DESIGN, SETTING, AND SUBJECTS: Rats were anesthetized and tracheostomy was performed at State University of New York Upstate Medical University. Arterial and venous lines, a peritoneal catheter, and a rectal temperature probe were inserted. Animals were randomized into 3 groups and followed up for 6 hours: spontaneous breathing ventilation (SBV, n = 5), continuous mandatory ventilation (CMV, n = 6), and APRV (n = 5). Rats in the CMV group were ventilated with VT of 10 cc/kg and PEEP of 0.5 cm H 2O. Airway pressure release ventilation was set with a P High of 15 to 20 cm H2O; PLow was set at 0 cm H2O. Time at PHigh (THigh) was 1.3 to 1.5 seconds and a TLow was set to terminate at 75% of the peak expiratory flow rate (0.11-0.14 seconds), creating a minimum 90% cycle time spent at PHigh. Bronchoalveolar lavage fluid and lungs were harvested for histopathologic analysis at necropsy. RESULTS: Acute lung injury/ARDS developed in the CMV group (mean [SE] Pao2/FiO2 ratio, 242.96 [24.82]) and was prevented with preemptive APRV (mean [SE] Pao 2/FIO2 ratio, 478.00 [41.38]; P < .05). Airway pressure release ventilation also significantly reduced histopathologic changes and bronchoalveolar lavage fluid total protein (endothelial permeability) and preserved surfactant proteins A and B concentrations as compared with the CMV group. CONCLUSIONS AND RELEVANCE: Continuous mandatory ventilation in normal rats for 6 hours with VT and PEEP settings similar to those of surgery patients caused ALI. Preemptive application of APRV blocked early drivers of lung injury, preventing ARDS. Our data suggest that APRV applied early could reduce the incidence of ARDS in patients at risk.