OBJECTIVE: With the advent of highly active antiretroviral therapy regimens, it is crucial to consider their long-term benefits to risk ratios among HIV-infected persons. The impact of protease inhibitors on the cardiovascular risk is controversial. DESIGN: This observational cohort was designed to investigate the cardiovascular impact of boosted atazanavir (ATV/r), a protease inhibitor that does not provide major dyslipidemia or insulin resistance. SETTING: This study was carried out at the University Hospital of Brest (France). PATIENTS: Among the 229 HIV-infected persons of the cohort, 33 cases treated by ATV/r-containing regimen since less than 6 months were compared to 99 age-matched and sex-matched ATV/r naive controls. INTERVENTION: None. MAIN OUTCOME MEASURE: The main outcome measure was carotid intima-media thickness (cIMT) at the baseline, 6, 12, and 18 months. RESULTS: Although the cIMT was not different at inclusion (0.633 ± 0.05 vs. 0.666 ± 0.09, P = 0.07), the cIMT course significantly decreased (P = 0.018) in cases at 18 months. The differences remained significant even after adjustment on the variables that differed between cases and controls (P < 0.1) at inclusion (high-density lipoprotein cholesterol, cardiovascular family history) and the cumulated and current exposure to the nucleosidic reverse transcriptase inhibitor, nonnucleosidic reverse transcriptase inhibitor, and protease inhibitor class. CONCLUSION: Despite similar HIV and cardiovascular characteristics at baseline, cIMT decreased after 6 months of follow-up among the patients exposed to ATV/r, even after adjustment for the exposure to the three antiretroviral classes. Considering the shortcomings of this study, especially the absence of randomization and the heterogeneity of the control group, the benefit of ATV/r treatment in patients with high cardiovascular should be confirmed by randomized trials.