Objectives: To evaluate the contribution of European genetic admixture (EUADM) to insulin resistance syndrome (IRS) in a multiethnic sample of children age 7-12 years, and to explore whether body fat affects this relationship. Study design: Anthropometric measurements and blood pressure were assessed in 243 children. After an overnight fast, an intravenous glucose tolerance test was conducted, and measures of fasting insulin/glucose, lipids, insulin sensitivity (SI), and acute insulin response to glucose (AIRg) were obtained. The proportion of EUADM was determined by maximum likelihood estimation using 140 ancestry informative markers. Subjects were stratified into tertiles according to the proportion of EUADM for analyses. Subjects were categorized as lean or obese using body fat percentage cutpoints (25% in boys, 30% in girls). Results: Among lean subjects (72%), the tertile representing the greatest proportion of EUADM was associated with higher SI (P <.001) and serum glucose (P <.05) and lower insulin (P <.05), AIRg (P <.001), high-density lipoprotein cholesterol (P = .05), and blood pressure (P <.05). However, among obese subjects, EUADM was associated only with SI (P <.05). Conclusions: Our results suggest that population differences in IRS likely have a genetic component, but that the influence of genetic background may be masked by obesity. © 2010 Mosby, Inc. All rights reserved.