INTRODUCTION: Unsuppressed viral load during antiretroviral therapy (ART) is associated with health decline and HIV transmission. Being overweight or obese increases the risk of non-communicable diseases, increasing the risk of multimorbidity in people living with HIV. Both ART effectiveness and obesity have been shown to be affected by socioeconomic, psychological and health related factors, but their interrelationships in South Africans living with HIV are not well known. METHODS: This was a secondary analysis of data from a randomised controlled trial of depression management in 2002 adults receiving ART. We investigated the effects of sociodemographic characteristics, comorbidities, depression symptoms (Patient Health Questionnaire-9 (PHQ-9)), functional disability (WHODAS-2.0), AIDS-related stigma and ART adherence on viral load non-suppression (viral load ≥1000 copies/ml) and on body mass index (BMI), at baseline (baseline) and on changes 12 months later, using longitudinal mixed effect logistic and linear regression models. Potentially confounding covariates were selected and adjusted for using least absolute shrinkage and selection operator (LASSO) inference. RESULTS: People with viral load non-suppression at baseline were more likely to be male, younger and to earn lower income. Health characteristics associated with viral load non-suppression at baseline were previous tuberculosis, having been on ART for less than 6 months or more than 10 years, and self-reported non-adherence to ART. Higher disability score and ART duration <6 months or >10 years at baseline were associated with an increasing likelihood of viral load non-suppression 12 months later. Higher BMI at baseline was associated with being female, being married, earning higher income and hypertension, no history of tuberculosis and not having viral load non-suppression. BMI increased from baseline to follow-up, and younger age was associated with a greater increase in BMI 12 months later. Depression symptom scores and stigma scores were not associated with viral load non-suppression or BMI. CONCLUSIONS: Viral load non-suppression was associated with lower BMI, most likely due to its effects on HIV-related illness. Viral load non-suppression and BMI were both associated with a variety of sociodemographic factors, while viral load non-suppression was also associated with disability and ART non-adherence. These findings together indicate subgroups of people with HIV who most need improved ART access and adherence support. Neither outcome was associated with severity of depression symptoms or self-reported stigma.ClinicalTrials.gov (NCT02407691), Pan African Clinical Trials Registry (201504001078347), South African National Clinical Trials Register (SANCTR) (DOH-27-0515-5048, NHREC 4048).