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Abstract Background Morbidity and mortality rates from chronic non-communicable diseases (CNCDs) are increasing globally. In Ghana, CNCDs account for 43% of all deaths. We examined the Health-Related Quality of Life (HRQoL) and associated factors among adults living with CNCDs in the Ho Municipality. Methods This was a health facility-based descriptive cross-sectional study among 432 adults living with cancer, diabetes, chronic kidney disease (CKD), stroke, and hypertension in the Ho Municipality of Ghana. The study adopted the EQ-5D-5L instrument and the Ugandan value set to compute respondents’ HRQoL index. Quantile regression models were used in analysing the data with STATA v17.0 at 95% Confidence Intervals, and statistical significance set at p