This paper assesses the levels of antiretroviral treatment (ART) adherence and mental health distress among study participants in a national behavioural HIV-sero prevalence study South Africa. The study was a cross-sectional population-based multi-stage stratified cluster random survey, (SABSSM V, 2017). Structured questionnaires were used to collect information on socio-demographics, HIV knowledge, perceptions, HIV testing and HIV treatment history. Study participants were tested for HIV infection, antiretroviral use, viral suppression, and ART drug resistance. A total of 2155 PLHIV aged 15 years or older who were on ART were included in the study. Incidence of either moderate or severe mental health distress was 19.7%. Self-reported ART adherence among study participants with no, mild, moderate, or severe mental distress was 82%, 83%, 86% and 78%, respectively. The adjusted odds ratio for ART non-adherence was 0.58 (95% CI 0.24; 1.40) for mild mental distress, 0.82 (95% CI 0.35; 1.91) for moderate mental distress and 2.19 (95% CI 1.14; 4.19) for severe mental distress groups compared to the no mental health distress group. The other factors that were associated with ART non-adherence in adjusted models included education level, alcohol use and province/region of residence. The study revealed that mental health remains a challenge to ART adherence in South Africa. To improve ART adherence, HIV continuum of care programs should include screening for mental health among people living with HIV.