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To determine whether gas exchange improvement in response to the prone position is associated with an improved outcome in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS).Retrospective analysis of patients in the pronation arm of a controlled randomized trial on prone positioning and patients enrolled in a previous pilot study of the prone position.Twenty-eight Italian and two Swiss intensive care units.We studied 225 patients meeting the criteria for ALI or ARDS.Patients were in prone position for 10 days for 6 hrs/day if they met ALI/ARDS criteria when assessed each morning. Respiratory variables were recorded before and after 6 hrs of pronation with unchanged ventilatory settings.We measured arterial blood gas alterations to the first pronation and the 28-day mortality rate. The independent risk factors for death in the general population were the Pao2/Fio2 ratio (odds ratio, 0.992; confidence interval, 0.986–0.998), the minute ventilation/Paco2 ratio (odds ratio, 1.003; confidence interval, 1.000–1.006), and the concentration of plasma creatinine (odds ratio, 1.385; confidence interval, 1.116–1.720). Pao2 responders (defined as the patients who increased their Pao2/Fio2 by ≥20 mm Hg, 150 patients, mean increase of 100.6 ± 61.6 mm Hg [13.4 ± 8.2 kPa]) had an outcome similar to the nonresponders (59 patients, mean decrease −6.3 ± 23.7 mm Hg [−0.8 ± 3.2 kPa]; mortality rate 44% and 46%, respectively; relative risk, 1.04; confidence interval, 0.74–1.45, p = .65). The Paco2 responders (defined as patients whose Paco2 decreased by ≥1 mm Hg, 94 patients, mean decrease −6.0 ± 6 mm Hg [−0.8 ± 0.8 kPa]) had an improved survival when compared with nonresponders (115 patients, mean increase 6 ± 6 mm Hg [0.8 ± 0.8 kPa]; mortality rate 35.1% and 52.2%, respectively; relative risk, 1.48; confidence interval, 1.07–2.05, p = .01).ALI/ARDS patients who respond to prone positioning with reduction of their Paco2 show an increased survival at 28 days. Improved efficiency of alveolar ventilation (decreased physiologic deadspace ratio) is an important marker of patients who will survive acute respiratory failure.