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Metabolic abnormalities including diabetes, dyslipidemia, hypertension, and abdominal obesity occur commonly in HIV patients, are associated with increased coronary artery calcification (CAC), and contribute to increased cardiovascular disease (CVD) in this population. We hypothesized that lifestyle modification (LSM) and metformin would improve CVD indices in HIV patients with metabolic syndrome.A randomized, placebo-controlled trial to investigate LSM and metformin, alone and in combination, over 1 year, among 50 HIV-infected patients with metabolic syndrome.We assessed CAC, cardiovascular and metabolic indices.Among the participants, duration of HIV-infection was 14 ± 1 year and duration of antiretroviral therapy was 6 ± 1 year. Metformin-treated patients demonstrated significantly less progression of CAC (−1 ± 2 vs. 33 ± 17, P = 0.004, metformin vs. placebo), whereas the effect of LSM on CAC progression was not significant (8 ± 6 vs. 21 ± 14, P = 0.82, LSM vs. no-LSM). Metformin had a significantly greater effect on CAC than LSM (P = 0.01). Metformin-treated patients also demonstrated less progression in calcified plaque volume (−0.4 ± 1.9 vs. 27.6 ± 13.8 μl, P = 0.008) and improved homeostatic model of assessment-insulin resistance (HOMA-IR) (P = 0.05) compared with placebo. Participants randomized to LSM vs. no-LSM showed significant improvement in HDL (P = 0.03), high-sensitivity C-reactive protein (hsCRP) (P = 0.05), and cardiorespiratory fitness. Changes in CAC among the four groups – no-LSM–placebo (43 ± 30); LSM–placebo (19 ± 7); no-LSM–metformin (1 ± 1) and LSM–metformin (−4 ± 6) – were different (P = 0.03 for ANOVA and linear trend across groups), and the majority of this effect was mediated by metformin. Results are mean ± SEM.Metformin prevents plaque progression in HIV-infected patients with the metabolic syndrome.