Antiretroviral therapy (ART) has significantly transformed the management of human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS), positively impacting the health-related quality of life (HRQoL) and life expectancy of people living with HIV and AIDS (PLWHA). HRQoL is a critical consideration for HIV and AIDS patients as it reflects their overall well-being and treatment outcomes. This study aimed to investigate the HRQoL of PLWHA receiving an ART regimen containing tenofovir, lamivudine, and dolutegravir at a tertiary hospital in Johannesburg, South Africa. This descriptive, quantitative, cross-sectional study included 103 patients who consented in writing to participate. Data was collected using WHOQOL HIV-BREF, socio-demographic, health characteristics, and adherence questionnaires. Participants who reported 'excellent' and 'very good' on the descriptive rating scale were considered to have optimal adherence (≥95 %). This study's statistical significance was set at