Extracorporeal carbon dioxide removal (ECCO2R) devices are increasingly used in treating acute-on-chronic respiratory failure caused by chronic lung diseases. There are no large studies that investigated safety, efficacy, and the independent association of prognostic variables to survival that could define the role of ECCO2R devices in such patients. This multicenter, multinational, retrospective study investigated the efficacy, safety of a single ECCO2R device (Hemolung) in patients with acute on chronic respiratory failure and identified variables independently associated with intensive care unit (ICU) survival. The primary outcome was improvement in blood gasses with the use of Hemolung. Secondary outcomes included reduction in tidal volume, respiratory rate, minute ventilation, survival to ICU discharge, and complication profile. Multivariable regression analysis was used to identify variables that are independently associated with ICU survival. A total of 62 patients were included. There was a significant improvement in pH and partial pressure of carbon dioxide in arterial blood (PaCO2) along with a reduction in respiratory rate, tidal volume, and minute ventilation with Hemolung therapy. The complication profile did not differ between survivors and nonsurvivors. Multivariable analysis identified the duration of Hemolung therapy to be independently associated with survival to ICU discharge (adjusted odds ratio = 1.21; 95% confidence interval [CI] = 1.040–1.518; p = 0.01).