The purpose of this study was to investigate relationships between inflammatory markers and components of a metabolic syndrome cluster in adolescents. This was a cross-sectional analysis of an Australian childhood cohort (n = 1,377) aged 14 years. Cluster analysis defined a “high-risk” group similar to adults with metabolic syndrome. Relevant measures were anthropometry, fasting insulin, glucose, lipids, inflammatory markers, liver function, and blood pressure. Of the children, 29% fell into a high-risk metabolic cluster group compared with 2% by a pediatric metabolic syndrome definition. Relative to the “low-risk” cluster, they had higher BMI (95% CI 19.5–19.8 vs. 24.5–25.4), waist circumference (centimeters) (95% CI 71.0–71.8 vs. 83.4–85.8), insulin (units per liter) (95% CI 1.7–1.8 vs. 3.5–3.9), homeostasis model assessment (95% CI 1.7–1.8 vs. 3.5–3.9), systolic blood pressure (millimeters of mercury) (95% CI 110.8–112.1 vs. 116.7–118.9), and triglycerides (millimoles per liter) (95% CI 0.78–0.80 vs. 1.25–1.35) and lower HDL cholesterol (millimoles per liter) (95% CI 1.44–1.48 vs. 1.20–1.26). Inflammatory and liver function markers were higher in the high-risk group: C-reactive protein (CRP) (P <0.001), uric acid (P <0.001), alanine aminotransferase (ALT) (P <0.001), and γ-glutamyl transferase (GGT) (P <0.001). The highest CRP, GGT, and ALT levels were restricted to overweight children in the high-risk group. Cluster analysis revealed a strikingly high proportion of 14 year olds at risk of cardiovascular disease–related metabolic disorders. Adiposity and the metabolic syndrome cluster are synergistic in the pathogenesis of inflammation. Systemic and liver inflammation in the high-risk cluster is likely to predict diabetes, cardiovascular disease, and nonalcoholic fatty liver disease.