Purpose To assess risk factors for type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) with the hypothesis that risk for T2DM in children would be associated with an increase in risk factors for CVD. Methods Subjects from a group of Mexican-American school children (aged 10-12 years) identified to be at risk for T2DM, and their siblings, were selected for this study. There were 68 children with acanthosis nigricans (AN+), and 71 without AN (AN-). Both AN+ and AN- children were assessed for T2DM and CVD risk factors. Probands and siblings were evaluated by physical examination, family history, and fasting serum parameters: glucose, insulin, body mass index (BMI), serum lipoproteins, and oxidized lipids. Data were analyzed by descriptive, univariate, and multivariate procedures. Results BMI, waist/hip ratio, systolic and diastolic blood pressure were all significantly higher (p < .002) in AN+, whereas Tanner stages were similar in both groups. Fasting serum glucose was in the normal range, whereas insulin was elevated in AN+ compared with AN- (30.0 ± 1.9 μU/mL vs. 14.8 ± 1.0 p < .0001). Insulin resistance as assessed by the homeostasis assessment model (HOMA-IR) was elevated in both groups, although higher among AN+ (p < .0001). High-density lipoprotein-cholesterol (HDL-C) was lower (6.2 mg/dL) in the AN+ group (p < .003). The lower HDL-C in AN+ was associated with elevated triglycerides and a higher serum total cholesterol TC/HDL-C ratio when contrasted with the AN- values (145.9 ± 7.6 mg/dL vs. 97.1 ± 0.07, p < .0001; 4.1 ± 0.2 vs. 3.4 ± 0.1, p < .0001, respectively). In addition to the high prevalence of overweight/obesity (BMI > 85th percentile) in this population (76.3%, 106/139), elevated insulin (59.7% >15 μU/mL), low HDL-C (27.3% <40 mg/dL), and elevated low-density lipoprotein cholesterol (LDL-C) (41.0% >100 mg/dL) were also detected. Conclusions: The altered metabolic pattern observed in this group of Mexican-American children is characteristic of metabolic syndrome, a condition associated with obesity and increased risk for both T2DM and CVD in adults. This study points to the value of BMI and acanthosis nigricans as easily accessible markers for children and nuclear families at increased risk for developing T2DM and CVD. © Society for Adolescent Medicine, 2004.