If homeostasis model assessment of insulin resistance (HOMA-IR) interactions with obesity (body mass index [BMI]) at ages 9 to 10 years predict aggregate metabolic syndrome risk factors at ages 18 to 19 years, this would identify novel avenues for primary prevention of metabolic syndrome. Our hypothesis was that HOMA-IR*BMI interactions at ages 9 to 10 years would predict aggregate metabolic syndrome risk factor z scores at ages 18 to 19 years in prospective studies of a biracial population of girls. Two centers in the National Heart, Lung, and Blood Institute Growth and Health Study measured serum insulin and glucose at ages 9 to 10 years and 5 metabolic syndrome risk factors at ages 18 to 19 years (triglyceride, high-density lipoprotein cholesterol, systolic/diastolic blood pressure, waist circumference, and glucose). Studies in Cincinnati, OH, included girls from public and parochial schools in the inner city, within-city residential neighborhoods, and suburban areas; and those in Washington, DC, included girls from a health maintenance organization. Girls (194 white, 281 black) were studied first at ages 9 to 10 years, then at ages 18 to 19 years. We assessed HOMA-IR*BMI interactions at ages 9 to 10 years with race-specific z scores for 5 metabolic syndrome risk factors at ages 18 to 19 years. The lowest summed z score (mean +/- SD) was observed for subjects in the lowest tertiles for both HOMA-IR and BMI (-1.15 +/- 2.05), and the highest z score (2.58 +/- 3.11) was for subjects in the highest tertiles for both HOMA-IR and BMI (P < .0001). For the top BMI tertile, there was a progressive increase in z score (increasing risk of metabolic syndrome) as HOMA-IR increased. Interaction of BMI with HOMA-IR at ages 9 to 10 years predicts aggregate metabolic risk score at ages 18 to 19 years, with progressive risk increments within the top BMI tertile as HOMA-IR increases, opening avenues for intervention to reduce both BMI and HOMA-IR at ages 9 to 10 years as a primary approach to prevention of metabolic syndrome at ages 18 to 19 years.