Background Research on health-related quality of life (HRQL) has become increasingly important in recent decades. However, the impact of both living conditions and the level of autonomy impairments on HRQL in COPD patients receiving non-invasive ventilation (NIV) is still unclear. Methods The Severe Respiratory Insufficiency Questionnaire (SRI) was used to measure HRQL in a prospective cohort of COPD patients in whom home NIV was already established. Data on sociodemographics, clinical characteristics and standardized levels of autonomy impairment were evaluated. A multiple linear regression analysis was performed to identify the factors associated with a reduced HRQL. Results A total of 137 patients (67.0 ± 7.8 years, 45% female) were assessed. The mean SRI Summary Score was 54.1 ± 16.9 (95%CI: 51.1–57.1; N = 127). Regular ambulatory care was provided in 76% of patients, but only 37% underwent pulmonary rehabilitation. Overall, 69% of patients lived with family members, while 31% lived alone (family situation). Autonomy impairment levels were most serious in 3%, serious in 14%, and significant in 29% of patients, while 54% had no impairments at all. Of note, higher levels of autonomy impairment were markedly associated with lower SRI scores (regression coefficient − 6.5 ± 1.1 per level; P < 0.001). In contrast, family situation (0.2 ± 3.0; P = 0.959), ambulatory care by a respiratory specialist (1.7 ± 3.6; P = 0.638), and pulmonary rehabilitation (− 0.8 ± 3.1; P = 0.802) did not appear to influence HRQL. Possible subgroup effects were evident for the factors “impaired autonomy” and “living in a nursing home” (P = 0.016). Conclusion A higher level of autonomy impairment has been identified as the major determinant of reduced HRQL in COPD-patients receiving long-term NIV, particularly in those living in a nursing home. Trial Registration German Clinical Trials Register (DRKS00008759).

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