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Postpneumonectomy acute respiratory failure leading to invasive mechanical ventilation carries a severe prognosis, especially when acute respiratory distress syndrome develops. The aim of this study was to describe the risk factors, management, and outcome of postpneumonectomy acute respiratory distress syndrome.We retrospectively reviewed the clinical files of patients undergoing pneumonectomy in a single center between 2005 and 2015. Risk factors for acute respiratory distress syndrome, management characteristics, and short- and long-term outcomes were assessed.Among the 543 patients undergoing pneumonectomy, 89 (16.4%) needed reintubation within the 30th postoperative day, including 60 (11%) who developed acute respiratory distress syndrome. At multivariate analysis, right-side pneumonectomy (odds ratio [OR], 2.75; 95% confidence interval [CI], 1.51-5.02; P = .0009) and higher Charlson Comorbidity Index (OR, 1.26; 95% CI, 1.07-1.49; P = .007) were identified as independent risk factors for acute respiratory distress syndrome. Operative mortality was 8.1% for all pneumonectomies, 43.8% (n = 39/89) in intubated patients, and 56.7% (34/60) in patients with acute respiratory distress syndrome. Mortality was higher in severe (25/36, 69.4%) than in mild or moderate acute respiratory distress syndrome (9/24, 37.5%, P = .014). Logistic regression identified 3 independent predictors of operative mortality in patients with acute respiratory distress syndrome: age (OR, 1.08; 95% CI, 1.01-1.15; P = .02), right pneumonectomy (OR, 5.97; 95% CI, 1.33-26.71; P = .02), and severe acute respiratory distress syndrome (OR, 7.19; 95% CI, 1.74-29.73; P = .006). Five-year survival was 17.6% for patients with acute respiratory distress syndrome.Acute respiratory distress syndrome is a severe early complication of pneumonectomy with a poor outcome. The low survival underlines the need for novel management strategies.