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Mechanical ventilation of patients with acute respiratory distress syndrome (ARDS) may contribute to pulmonary injury and systemic inflammation. The objective of this study was to examine the safety and efficacy of a recruitment maneuver that rapidly improves atelectasis and oxygenation, and in so doing may reduce the potential for ventilator-induced lung injury. Nineteen patients with severe ARDS (defined as PaO2:FiO2 ≤ 150) from diverse etiologies were turned prone and a positive pressure of 40 cmH2O was applied for a period of 90 seconds. This pressure was increased in 5 cmH2O increments in subsequent maneuvers to a maximum of 50 cmH2O if there was an inadequate initial response. Subsequently pressure-limited mechanical ventilation with a PEEP of 15 cmH2O was instituted to prevent derecruitment. Peak pressures were maintained at ≤35 cmH2O. Outcome measures were oxygenation index, PaO2:FiO2 ratio, and alveolar-arterial oxygen difference. The oxygenation index decreased from a median of 31 cmH2O/mmHg to 14 cmH2O/mmHg immediately after recruitment and to 11 cmH2O/mmHg (p < 0.0001) 24 hours later. The A-aDO2 improved from 454 mmHg to 128 mmHg (p < 0.0001) and the PaO2:FiO2 ratio from 75 to 218 (p < 0.0001) 24 hours later. Twenty-five percent of patients had PaO2:FiO2 ratios of more than 300 mmHg at 24 hours. Mean airway pressure increased by 3 cmH2O initially, from 23 cmH2O to 26 cmH2O as a consequence of the increase in PEEP, but this had decreased to 25 cmH2O after 24 hours. There were no significant complications. Rapid reductions in FiO2 can be achieved safely by the implementation of a relatively simple recruitment technique.