Chronic obstructive pulmonary disease (COPD) is expected to be the 3rd leading cause of death worldwide by 2020. Despite improvements in survival by using acute non-invasive ventilation (NIV) to treat patients with exacerbations of COPD complicated by acute hypercapnic respiratory failure (AHRF), these patients are at high risk of readmission and further life-threatening events, including death. Recent studies suggested that NIV at home can reduce readmissions, but in a small proportion of patients, and with a high level of expertise. Other studies, however, do not show any benefit of home NIV. This could be related to the fact that respiratory failure in patients with stable COPD and their response to mechanical ventilation are influenced by several pathophysiological factors which frequently coexist in the same patient to varying degrees. These pathophysiological factors might influence the success of home NIV in stable COPD, thus long-term NIV specifically adapted to a patient’s “phenotype” is likely to improve prognosis, reduce readmission to hospital, and prevent death. In view of this conundrum, Rescue2-monitor (R2M), an open-label, prospective randomized, controlled study performed in patients with hypercapnic COPD post-AHRF, will investigate the impact of the quality of nocturnal NIV on the readmission-free survival. The primary objective is to show that any of 3 home NIV strategies (“rescue,” “non-targeted,” and “targeted”) will improve readmission-free survival in comparison to no-home NIV. The “targeted” group of patients will receive a treatment with personalized (targeted) ventilation settings and extensive monitoring. Furthermore, the influence of comorbidities typical for COPD patients, such as cardiac insufficiency, OSA, or associated asthma, on ventilation outcomes will be taken into consideration and reasons for non-inclusion of patients will be recorded in order to evaluate the percentage of ventilated COPD patients that are screening failures. ClinicalTrials.gov NCT03890224 . Registered on March 26, 2019.