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Objective This study aimed to assess health-related quality of life (HRQoL) and identify associated factors among patients with chronic obstructive pulmonary disease (COPD) attending selected hospitals in Addis Ababa, Ethiopia.Design and setting A hospital-based multicentre cross-sectional study was conducted among 205 patients with COPD attending the chest clinics of selected hospitals in Addis Ababa, Ethiopia, from June 2023 to December 2023.Participants A total of 205 patients with COPD who had follow-up at outpatient departments of the chest clinic of the selected hospitals were included in the study.Main outcome measures The main outcome of this study was HRQoL, which was assessed using the validated COPD Assessment Test-Amharic version (CAT-Am). Data analysis was performed using Stata version.17, and multivariable linear regression was employed to examine the relationship between HRQoL and independent variables. Variables with p-values <0.05 at a 95% CI were considered statistically significant.Results The mean score of the overall CAT-Am was 20.24±8.13. Older age (β=0.11, 95% CI: 0.04 to 0.17), poor social support (β=2.49, 95% CI: 0.74 to 4.24), biomass fuel exposure (β=4.57, 95% CI:3.17 to 5.97), Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages 2, 3 and 4 (β=2.12, 95% CI: 0.23 to 4.01; β=3.38, 95% CI: 1.11 to 5.66; β=5.20, 95% CI: 2.37 to 8.05, respectively), presence of comorbidity (β=4.03, 95% CI: 2.48 to 5.59), increased number of hospitalisations in the past year (β=2.78, 95% CI: 1.68 to 3.88), increased number of prescribed medications (β=0.40, 95% CI: 0.10 to 0.70), low medication adherence (β=2.79, 95% CI: 1.13 to 4.46), and moderate medication adherence (β=3.38, 95% CI: 1.65 to 5.11) were negatively associated with HRQoL.Conclusion and recommendations In this study, patients with COPD had poor HRQoL, which indicates that patients need multidisciplinary interventions. Older age, poor social support, an increased number of prescribed medications, an increased number of hospitalisations in the past year, biomass fuel exposure, low and moderate medication adherence, GOLD severity stages 2, 3 and 4, and the presence of comorbidities require close follow-up to improve HRQoL. Further research should evaluate targeted strategies to address these determinants.