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Lipid disorders associated with the use of protease inhibitors may contribute to the premature development of atherosclerosis. The purpose of the present study was to determine whether the administration of a protease inhibitor-containing regimen to middle-aged (30–50 years) HIV-infected individuals for 6 months or longer is associated with an increased prevalence of atherosclerosis.High-resolution B-mode ultrasound imaging was used to visualize the femoral and carotid arteries of 68 HIV-negative and 168 HIV-infected individuals, including 136 patients who had received protease inhibitors for 26.8 ± 8.9 months (mean ± SD). Atherogenic plaques were defined as a thickening of the intima–media ≥ 1200 mm.The proportion of participants with one or more plaques was higher in the HIV-infected group in comparison with the HIV-negative group (55 versus 38%;P = 0.02), and so was the prevalence of cigarette smoking (61 versus 46%;P = 0.03) and hyperlipidaemia (56 versus 24%;P < 0.001). The presence of plaque was independently associated with age, male gender, plasma low-density lipoprotein cholesterol levels and smoking. In univariate logistic regression analysis, an association was also found with HIV infection. Among HIV-infected subjects protease inhibitor therapy was not associated with the presence of plaque.A large proportion of the middle-aged HIV-infected individuals examined during this study had one or more atherosclerotic plaques within the femoral or carotid arteries. The presence of peripheral atherosclerosis within this population is not associated with the use of protease inhibitors, but rather with ‘classic’ cardiovascular risk factors such as smoking and hyperlipidaemia, which are amenable to interventions.