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Thymidine analogues (TA) and didanosine (ddI) have been associated with redistribution of body fat from subcutaneous (SAT) to visceral (VAT) adipose tissue, which, in turn, is a risk factor for cardiovascular disease (CVD). We explored differences in adipose tissue distribution between people living with HIV (PLWH) with prior exposure to TA and/or ddI, without exposure, and uninfected controls and the association with CVD risk factors.761 PLWH from the COCOMO study and 2,283 age- and sex-matched uninfected controls from the CGPS study were included. PLWH were stratified according to prior exposure to TA and/or ddI. VAT and SAT were determined by abdominal CT-scan. Hypotheses were tested using regression analyses.Exposure to TA and/or ddI was associated with 21.6 cm2 larger VAT (13.8–29.3) compared to HIV infection without exposure. HIV-negative status was associated with similar VAT compared to HIV infection without exposure. Cumulative exposure to TA and/or ddI (3.7 cm2 per year [2.3–5.1]), but not time since discontinuation (−1.1 cm2 per year [−3.4–1.1]), was associated with VAT. Prior exposure to TA and/or ddI was associated with excess risk of hypertension (aOR 1.62 [1.13–2.31]), hypercholesterolemia (aOR 1.49 [1.06–2.11]), and low HDL (aOR 1.40 [0.99–1.99]).This study suggests a potentially irreversible and harmful association of TA and ddI with VAT accumulation, which appears be involved in the increased risk of hypertension, hypercholesterolemia, and low HDL found in PLWH with prior exposure to TA and/or ddI, even years after treatment discontinuation.