Human Immunodeficiency Virus (HIV) is a chronic infectious disease, and without antiretroviral therapy (ART), it is associated with comorbidities. The prevalence of comorbidities, adherence to ART and quality of life (QoL) of HIV patients were studied. A cross-sectional study design involving 360 HIV patients from two ART clinics across the Tamale metropolis was employed. Socio-demography, adherence to therapy, and QoL data were taken with the help of a questionnaire and analyzed using SPSS version 24. The prevalence of comorbidities was 30.3% (109), with Hepatitis B infection (73, 20.3%) being the most prevalent. Adherence levels were high (192, 53.3%), moderate (108, 30.0%) and low (60, 16.7%). Overall, QoL was excellent amongst 149 (41.4%), good in 169 (46.7%), and poor in 42 (11.7%) respondents. Marital status, presence or absence of HIV symptoms, adherence level to ART and overall QoL, especially Physical, Psychological, and independence domains (p < 0.05), were factors associated with the presence of comorbidities. There is a high level of comorbidities among persons living with HIV (PLWH) in the Tamale metropolis influenced by QoL and adherence to ART. We recommend a multifaceted approach to the management of PLWH.