Abstract Background Prospective investigations on the risk of cardiovascular disease among youth with perinatally acquired human immunodeficiency virus (PHIV) in sub-Saharan Africa are lacking. Methods A prospective observational cohort study was performed in 101 youth (aged 10–18 years) with PHIV and 97 who were human immunodeficiency virus (HIV) uninfected (HIV−), from 2017 to 2021 at the Joint Clinical Research Center in Uganda. Participants with PHIV were receiving antiretroviral therapy (ART) and had HIV-1 RNA levels ≤400 copies/mL. The common carotid artery intima-media thickness (IMT) and pulse wave velocity (PWV) were evaluated at baseline and at 96 weeks. Groups were compared using unpaired t-test, and potential predictors of IMT and PWV were assessed using quantile regression. Results Of the 198 participants recruited at baseline, 168 (89 with PHIV, 79 HIV−) had measurements at 96 weeks. The median age (interquartile range) age was 13 (11–15) years; 52% were female, and 85% had viral loads <50 copies/mL that remained undetectable at week 96. The baseline mean common carotid artery IMT was slightly higher in participants with PHIV compared with controls (P < .01), and PWV did not differ between groups (P = .08). At week 96, IMT decreased and PWV increased in the PHIV group (P ≤ .03); IMT increased in the HIV− group (P = .03), with no change in PWV (P = .92). In longitudinal analyses in those with PHIV, longer ART duration was associated with lower PWV (β = .008 [95% confidence interval, −.008 to .003]), and abacavir use with greater IMT (β = .043 [.012–.074]). Conclusions In healthy Ugandan youth with PHIV, virally suppressed by ART, the common carotid artery IMT did not progress over 2 years. Prolonged and early ART may prevent progression of subclinical vascular disease, while prolonged use of abacavir may increase it.