BACKGROUND: Non-invasive ventilation (NIV) is a well-established treatment for chronic hypercapnic respiratory failure (CHRF). While studies have demonstrated benefits for mortality, hospitalization rates, and health related quality of life (HRQL), evidence is particularly sparse regarding HRQL determinants in the older population. METHODS: In a prospective, monocentric observational study, HRQL was assessed using the established Severe Respiratory Insufficiency Questionnaire (SRI). The study was prospectively registered in the German Clinical Trials Register on 17 June 2015 under the registration number DRKS00008759. Patients were categorized into two age-based groups: older patients (≥ 65 years) and younger patients (< 65 years). Multiple linear regression analyses were used to analyze factors on HRQL, including SRI scores, anemia, autonomy impairment, exacerbation history and other factors. RESULTS: 237 Patients with COPD with CHRF receiving NIV therapy were included. The mean SRI summary score was 49.9 ± 16.8. with 23.2% (N = 55) suffering from anemia and 36.7% (N = 87) experiencing ≥ 2 exacerbations annually. Autonomy impairment was observed in 49.4% (N = 117) of patients. The updated Charlson Comorbidity Index (uCCI) was 2.2 ± 1.86. No significant differences were found in SRI Summary Scale scores between age groups (p = 0.581), but notable disparities were present in the uCCI (p = 0.014). Multiple regression analysis revealed a negative association of exacerbation history (Young group: -9.2; 95% CI = -14.8/ -3.55 vs. Older group: -6.17; 95% CI = -11.91/ -0.43) and level of autonomy impairment (e.g. Level of Care 2 Young group: -13.91; 95% CI = -21.4/ -6.43 vs. Older group: -14.94; 95% CI = -22.64/ -7.24) on SRI scores with age-related differences. Anemia only had a negative association on the SRI scores in younger patients with COPD (Young group: -7.9; 95% CI = -14.0/ -1.75 vs. Older group: -1.78; 95% CI = -9.21/ 5.65). DISCUSSION: Frequent exacerbations and a higher level of autonomy impairment had a negative association on HRQL across all ages. However only higher levels of impairment (≥ 2) have a detrimental impact on older patients. Anemia was a negative HRQL factor in younger patients, where it was more prevalent. Overall, HRQL was found to be comparably favorable in both older and younger patients, despite age-specific differences in influencing factors. REGISTRATION OF THE CLINICAL TRIAL: The study from which the data were analyzed was prospectively registered in the German Clinical Trials Register (DRKS00008759) on June 17, 2015.