Insulin resistance (IR) is a pathophysiological construct that derives a series of metabolic disturbances that promote cardiometabolic dysfunction. This study evaluated mediating and modifying effects of homeostatic model assessment-based IR (HOMA-IR) on the association between sugar-sweetened beverage (SSB) consumption and a constellation of adolescent cardiometabolic abnormalities. Comprehensive data on sociodemographics, diet, physical activity, and anthropometric and biochemical parameters for 1454 adolescents were obtained from a large-scale representative study for adolescent metabolic syndrome (MetS) conducted in Taiwan. The original (HOMA1-IR) and updated nonlinear (HOMA2-IR) HOMA-IR indicators were used as IR biomarkers. Principal component (PC) analysis was employed to create reduced groups of variables and risk scores for retained PCs. Higher SSB intake was associated with higher levels of HOMA1-IR and HOMA2-IR, and the two IR biomarkers were positively correlated with metabolic dysfunction clustering. Compared with SSB nondrinkers, adolescents who consumed >500 mL/day of hand-shaken high-fructose corn syrup beverages (HHB) had a 0.22 increase in the number of abnormal MetS components, and HOMA-IR mediation explained 33.9-37.9% of the effect. IR biomarkers accounted for 26.5-31.0% of the relationship between >500 mL/day of SSB consumption and bodyweight-enhanced PC scores. The effects of HOMA-IR indicators on all bodyweight-related factors were consistently intensified among >350 mL/day HHB drinkers (all P  < 0.05). Fructose-rich SSB intake correlates with a constellation of cardiometabolic abnormalities in adolescents, and this association may be partly mediated by HOMA-IR levels. The adverse effects of HOMA-IR on bodyweight-associated cardiometabolic risk factors depend on the type of SSB consumption, with enhanced risks observed in the intake of high amounts of HFCS-containing SSBs.