Abstract Background: The association of highly active antiretroviral therapy (HAART) regimens that include protease inhibitors (PIs) with metabolic and somatic disorders has raised concerns about the possibility of an increased risk of coronary artery disease (CAD) in patients with HIV infection. Objective: The aim of this study was to assess the incidence of CAD in previously untreated HIV infected outpatients who received reverse transcriptase inhibitors with or without PIs. Methods: In this open-label, multicenter, prospective, observational trial, previously untreated and asymptomatic HIV-infected Italian patients were followed to assess the incidence of CAD (primary end point) according to the HAART regimen they received: 2 nucleoside analogue reverse transcriptase inhibitors (NRTIs) in combination with PIs (group PI+) or 1 non-nucleoside reverse transcriptase inhibitor in combination with 2 NRTIs (group PI-). Patients underwent clinical examination and laboratory testing every 4 months. Results: A total of 1551 HIV-infected patients (994 [64%] men; median age, 35 years; range, 22–50 years) were followed for a median 36 months (range, 34–42 months). The cumulative annual incidence of CAD-related events was 9.8/1000 in group PI+ and 0.8/1000 in group PI- ( P < 0.001). The annual incidence of myocardial infarction was 5.1/1000 in group PI+ and 0.4/1000 in group PI- ( P < 0.001). Independent of patient age, the incidence of CAD was greater among men ( P < 0.001) and patients who smoked >20 cigarettes per day ( P < 0.001). Lipodystrophy and metabolic alterations were observed in 62% of patients in group PI+ and in 4% of patients in group PI- ( P < 0.001). Of 23 patients receiving PIs who developed CAD, 17 (73.9%) had lipodystrophy and all 23 had hypertriglyceridemia and hypercholesterolemia. Conclusions: According to our findings, HAART that includes PIs may accelerate the onset of CAD-related events in young, male, heavy smokers who develop metabolic disorders and lipodystrophy during therapy. Patients with increased coronary risk should receive careful cardiac monitoring if treated with PIs.