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Introduction: The effectiveness of non‐invasive mechanical ventilation (NIV) in the management of COPD patients suffering from acute respiratory failure (ARF) as a consequence of exacerbation of the disease, is well established. However, data on long‐term outcomes and their predictors, including the individual response to NIV, are scarce. Objectives: To investigate predictors for short‐ and long‐term mortality in this study population. Methods: A retrospective cohort study was performed including all patients admitted to the Medium Respiratory Care Unit of Maastricht University Medical Center in Maastricht, the Netherlands, with hospitalized exacerbation of COPD (H‐ECOPD) with ARF requiring NIV for the first time between January 2009 and December 2011. An extensive number of potential predictors of outcomes, including the response to NIV, were determined on admission and during hospitalization. Univariate and multivariate logistic regression was used for statistical analysis. Results: Seventy‐eight consecutive patients with moderate to severe COPD (mean age 71.0 ± 10.7 years; 48.7% males) were included; In‐hospital, 1‐year and 2‐year mortality rates were 14.1%, 43.6% and 56.4%, respectively. Independent risk factors for 2‐year mortality were: advanced age (odds ratio(OR) 1.025; confidence interval (CI) 1.002‐1.049; P = 0.037), prolonged NIV use more than 8 days (OR:1.054;CI:1.006‐1.104; P = 0.027) and no successful response to NIV (OR:2.392;CI:1.297‐4.413; P = 0.005). Conclusion: Patients with an H‐ECOPD requiring NIV for the first time, constitute a severely ill patient group with high in‐hospital and 2‐year mortality. This study identified advanced age, NIV use more than 8 days and unsuccessful response to NIV as clinical important independent predictors for long‐term mortality. [ABSTRACT FROM AUTHOR]