OBJECTIVE: Impaired endothelial function was demonstrated in HIV-infected persons on protease-inhibitor (PI)-containing antiretroviral therapy, probably due to altered lipid metabolism. Atazanavir is a PI causing less atherogenic lipoprotein changes. We studied whether endothelial function improves after switching from other PI to atazanavir. DESIGN: Randomized, observer-blind, treatment-controlled trial. SETTING: Three university-based outpatient clinics. PATIENTS: 39 HIV-infected persons with suppressed viral replication on PI-containing regimens and fasting LDL-cholesterol >3mmol/L. INTERVENTION: Patients were randomized either to continue the current PI or change to unboosted atazanavir. MAIN OUTCOME MEASURES: Endpoints at week 24 were endothelial function assessed by flow-mediated vasodilation (FMD) of the brachial artery, lipid profiles, high sensitive C-reactive protein, malondyaldehyde, total antioxidative capacity and oxidized LDL. RESULTS: Baseline characteristics and mean FMD values of the two treatment groups were comparable (3.9+/-1.8% on atazanavir vs. 4.0+/-1.5% in controls). After 24 weeks' treatment, FMD decreased to 3.3+/-1.4% and 3.4+/-1.7%, respectively (all p=n.s.). Total cholesterol improved in both groups (p=<0.0001 and p=0.01, respectively) but changes were more pronounced on atazanavir (p=0.05, changes between groups). HDL and triglyceride levels improved on atazanavir (p=0.03 and p=0.003, respectively) but not in the control group. Serum inflammatory and oxidative stress parameters did not change; oxidized LDL improved significantly in the atazanavir group. CONCLUSIONS: The switch from another PI to atazanavir among treatment experienced patients did not result in improvement of endothelial function despite significantly improved serum lipids. Not only atherogenic lipid profiles but also direct effects of reverse transcriptase inhibitor plus PI-containing combination on the endothelium may affect vascular function. ClinicalTrials.gov Identifier: NCT00447070.