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This study aimed to examine the prospective association of three different measures of adiposity and cardiorespiratory fitness (CRF) with 2-year change in cardiovascular disease (CVD) risk factors in children. Two-year longitudinal data in schoolchildren aged 7–11 years (n= 365–729) was used. Total body fat (TBF) from dual-energy x-ray absorptiometry, body mass index (BMI), waist circumference (WC), CRF, blood samples, and blood pressure were obtained in 2008 and 2010 in the Childhood Health, Activity, and Motor Performance School Study in Denmark (CHAMPS study-DK). Greater adiposity at baseline was associated with increased CVD risk factor levels at follow-up. The magnitudes of associations were similar regardless of adiposity measure [TBF%: β 0.30, 95% confidence interval (CI): 0.21–0.39; BMI: β 0.24, 95% CI: 0.14–0.33; WC: β 0.20, 95% CI: 0.10–0.31], and no evidence of nonlinear relationships was observed. We found less strong associations of CRF with increase in CVD risk factor levels after adjusting for adiposity; however, increasing CRF was still favorably associated with decrease in CVD risk factor levels among boys. Results suggest that any effort to shift the population distribution of adiposity downward would be valuable for early CVD prevention. The association of CRF with CVD risk factors was largely explained by adiposity, particularly among girls.