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Background Cumulative data from several studies suggest that HIV-infected populations have a 2-fold increased cardiovascular risk. Evidence is also pointing to a link between HIV and early vascular changes, including endothelial dysfunction and subclinical atherosclerosis. There is a paucity of data from sub-Saharan Africa (the epicenter of the global HIV burden and a region with a rapidly increasing cardiovascular disease [CVD] incidence); furthermore, the contribution of specific combination ART (c-ART) regimens to HIV-related CVD and early vascular changes remain unclear. Purpose To investigate the association between HIV-infection, c-ART (TDF+FTC+EFV), CVD risk and vascular markers of CVD in an adult cohort in South Africa. Methods Cross-sectional study, participants assigned to 3 groups: HIV-free (HIV−), HIV-infected ART naïve (HIV+/−) and HIV-infected on ART (HIV+/+). Data collection: demographic information, anthropometrics, CVD risk factors, and blood chemistry. Vascular endpoints assessed: brachial artery flow-mediated dilatation (FMD), carotid intima-media thickness (C-IMT) and retinal microvascular calibers. Results Cohort size: n=427 (HIV− n=148; HIV+/− n=69; HIV+/+ n=210), mean age: 39.4 years, 68.9% females. Analysis of cardiovascular risk showed no differences in smoking and alcohol consumption, and blood pressure was unaffected by HIV-status. The untreated HIV group had a high % participants with clinically low HDL-cholesterol levels, whereas c-ART seemed to reduce the prevalence (HIV+/−: 58% vs 31% in HIV− and 26% in HIV+/+; p Conclusions Combination ART consisting of TDF+FTC+EFV conferred vascular protection in HIV-infected participants as shown by improved endothelial function (increased FMD) and smaller CRVE compared to ART naïve counterparts. There was no evidence of subclinical atherosclerosis involvement (C-IMT). The vasculoprotective effects in the treated group were supported by a favourable HDL-cholesterol profile, despite unchanged inflammation (hs-CRP), and evidence of renal and hepatic impairment. Acknowledgement/Funding Dept of Science and Technology (South Africa); National Research Foundation (South Africa); Belgian Science Policy, Belgium; Austrian Grants Agency.