Background. The association between the use of highly active antiretroviral therapy (HAART) and an increased risk of metabolic syndrome and cardiovascular disease remains unclear. Methods. We conducted a prospective, cross-sectional study of the risk factors associated with metabolic syndrome and cardiovascular disease among patients from an urban outpatient human immunodeficiency virus (HIV) clinic. Evaluation included laboratory data that were obtained after an overnight fast and a health survey that assessed traditional risk factors associated with cardiovascular disease, HIV-related factors, and comorbidities. Data collected were compared with data files from a cohort from the National Health and Nutrition Examination Survey (NHANES; 2001-2002) of persons who were seronegative for HIV infection who were matched for age, sex, race, and tobacco use. Results. Four hundred seventy-one HIV-infected subjects provided complete data. The overall prevalence of metabolic syndrome was similar between the group HIV-infected patients and the group of persons who were seronegative for HIV infection (25.5% vs. 26.5%, respectively), although the HIV-infected patients had a significantly smaller waist circumference, lower body mass index, lower high-density lipoprotein cholesterol levels, higher triglyceride levels, and lower glucose levels, compared with the subjects from the NHANES cohort. Framingham 10-year risk scores were also similar between the 2 groups. HIV-infected patients with metabolic syndrome were more likely to be diabetic, older, and white and have a high CD4 cell count and body mass index, compared with patients without metabolic syndrome (P<.05 for all). The type or duration of antiretroviral therapy was not an independent risk factor for metabolic syndrome. Conclusions. The prevalence of metabolic syndrome is high among HIV-infected persons, but not higher than the prevalence among HIV-uninfected persons. Traditional risk factors play a more significant role in the development of metabolic syndrome than do HIV treatment-associated factors. © 2007 by the Infectious Diseases Society of America. All rights reserved.