Patients with end-stage chronic obstructive pulmonary disease (COPD) often develop persistent hypoxic or hypercapnic respiratory failure, or a combination of both. Ventilatory support, in terms of a long-term high-flow nasal cannula (LT-HFNC) and long-term non-invasive ventilation (LT-NIV), may be indicated. Often, clinicians choose either one or the other. This paper explores combined treatment with LT-HFNC and LT-NIV in a real-life setting. In total, 33 patients with COPD and persistent respiratory failure were included in this study. Of those, 17 were initiated on LT-HFNC and used it for 595 (374) days and 16 were initiated on LT-NIV and used it for 558 (479) days. On average, patients used respiratory support continuously for 908 (586) days. Baseline characteristics were comparable, apart from PaCO2at first ventilatory support initiation (LT-HFNC/LT-NIV 7.1 (1.1) kPa/8.8 (0.9) kPa respectively (p= 0.002)). Both groups experienced a reduction in hospitalizations in the first twelve months after treatment initiation, compared to the twelve months before (LT-HFNCp= 0.022 and LT-NIVp= 0.014). In total, 25% of LT-NIV patients stopped treatment after HFNC initiation due to intolerance and 59% stopped LT-HFNC treatment 126 (36) days after LT-NIV initiation as monotherapy was sufficient. In 44% of these patients, LT-HFNC was re-initiated at the end of life. At the time of analysis, 70% of patients had died. In the last three months of life, patients stopped using LT-NIV, whereas 91% used LT-HFNC. In conclusion, the combined use of LT-NIV and LT-HFNC reduced hospitalizations in patients with COPD and persistent respiratory failure. The study indicates that LT-HFNC is well tolerated, and better tolerated than LT-NIV at the very end stages of COPD.