The mild chronic inflammatory state associated with obesity may be an important link between adiposity and insulin resistance (IR). In a sample of 137 overweight and obese Chilean adolescents, we assessed associations between high-sensitivity C-reactive protein (hs-CRP), IR and adiposity; explored sex differences; and evaluated whether hs-CRP mediated the relationship between adiposity and IR. Positive relationships between hs-CRP, IR and 2 measures of adiposity were found. Hs-CRP was associated with waist circumference (WC) in boys and fat mass index (FMI) in girls. Using path analysis, we found that hs-CRP mediated the relationship between adiposity (WC and FMI) and the homeostatic model assessment of insulin resistance (HOMA-IR) (p < 0.05) in both sexes. Our novel finding is that inflammation statistically mediated the well described link between increased adiposity and IR.