OBJECTIVE - To investigate the association of insulin resistance and clinically defined metabolic syndrome (MetS) with subclinical atherosclerosis and examine whether these relationships vary by race/ethnicity or sex. RESEARCH DESIGN AND METHODS - Subclinical atherosclerosis was assessed by coronary artery calcium (CAC) and carotid intima-medial thickness (IMT) in 5,810 participants without diabetes in the Multi-Ethnic Study of Atherosclerosis, a cohort of adults aged 45-84 years without prior cardiovascular disease (CVD). Fasting insulin and glucose were utilized to estimate insulin resistance by the homeostasis model assessment of insulin resistance (HOMA-IR) index, and the revised National Cholesterol Education Program definition of MetS was utilized. Multivariable linear or relative risk regression was used to analyze the association between HOMA-IR and subclinical atherosclerosis and assess its independence from MetS components. RESULTS - HOMA-IR was associated with increased IMT after adjustment for demographics (age, site, and education), smoking, education, and LDL cholesterol in each ethnic group, except Hispanic subjects, and in both men and women. After further adjusting for nonglucose MetS components, HOMA-IR was not associated with increased IMT. Subjects in the highest quintile of HOMA-IR had an elevated prevalence of CAC in each ethnic group and both sexes, after adjustment for demographics, smoking, and LDL but not after further adjustment for nonglucose MetS components. Among those with detectable CAC, there was no significant relationship between HOMA-IR and the amount of CAC. CONCLUSIONS - Although HOMA-IR was associated with increased subclinical atherosclerosis, the association was not independent of the risk factors that comprise MetS. Determination of HOMA-IR is unlikely to contribute to improved determination of risk of subclinical CVD.