OBJECTIVE: To determine risk factors for cardiovascular disease (CVD) in children infected with human immunodeficiency virus (HIV) compared with nationally representative controls from 2003-2004 National Health and Nutrition Examination Survey (NHANES) data. STUDY DESIGN: A prospective, longitudinal analysis of CVD risk factors in 42 HIV-infected children compared with NHANES controls, with multivariable modeling of demographic, disease-specific, and treatment-related factors contributing to cardiac risk in the HIV cohort. RESULTS: The 42 children infected with HIV were initially an average of 10.1 years old; 68% were Centers for Disease Control and Prevention pediatric HIV disease stage B or C, and 76% were receiving highly active antiretroviral therapy (HAART). Compared with age- and sex-adjusted NHANES controls, the children infected with HIV had lower weight (-0.46 standard deviation [SD] vs +0.54 SD; P < .001), height (-0.62 SD vs +0.26 SD; P < .001), and body mass index (-0.09 SD vs +0.51 SD; P < .001), a higher level of triglycerides (136 mg/dL vs 90 mg/dL; P < .001), and a lower level of high-density lipoprotein (HDL) cholesterol (47 mg/dL vs 54 mg/dL; P < .001). Protease inhibitor therapy was independently associated with higher triglyceride (P = .02) and low-density lipoprotein cholesterol levels (P = .04) and lower HDL cholesterol level (P = .02); nonnucleoside reverse-transcriptase inhibitor therapy was associated with lower visceral fat (P = .01) and higher HDL cholesterol level (P = .005). CONCLUSIONS: Children infected with HIV have adverse cardiac risk profiles compared with NHANES controls. Antiretroviral therapy has a significant influence on these factors.