<p>The prevalence of both prediabetes and cardiovascular diseases (CVD) is a public health concern in high-risk individuals using HIV pre-exposure prophylaxis (HIV-PrEP) treatment. The combined effect of prediabetes and HIV-PrEP use on endothelial function remains underexplored. Hence, the aim of this study was to investigate the effects of emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) on endothelial function, oxidative stress, inflammation and lipid markers. Prediabetes was induced using a high-fat high-carbohydrate diet over a 20-week period. Prediabetes diagnosis was confirmed using fasting blood glucose and an oral glucose tolerance test. FTC/TDF was orally administered to the rats for a further 12 weeks. Biochemical analysis was performed using colorimetric assays. The prediabetic animals had higher fasting blood glucose (FBG), vascular endothelial growth factor A (VEGF-A), endothelin-1(ET-1), nitric oxide (NO), NO/ET-1 ratio, hydrogen peroxide (H₂O₂), interleukin-6, tumour necrosis factor α (TNF-α), triglycerides(TG), low-density lipoprotein cholesterol (LDL-C), endothelial nitric oxide synthase (eNOS), total antioxidant capacity (TAOC) and lower high-density lipoprotein cholesterol (HDL-C) when compared to the non-prediabetic control. However, the FTC/TDF treatment increased VEGF-A, HDL-C, LDL-C and it reduced TGs, NO, NO/ET-1 ratio, H₂O₂, eNOS, TAOC, interleukin-6, TNF-α and had minimal effect on FBG and ET-1 levels in prediabetic animals .In the non-prediabetic state, FTC/TDF treatment increased VEGF-A, ET-1, NO, NO/ET-1 ratio, H₂O₂ and interleukin-6 while decreasing eNOS, TAOC, TNF-α and HDL-C and it had a minimal effect on FBG, LDL-C and TGs. FTC/TDF treatment could increase the risk of cardiovascular complications via oxidative stress and endothelial dysfunction. Further studies are needed to fully understand the molecular mechanisms underlying these observed effects.</p>