Objective To examine the association between cardiorespiratory fitness (CRF) at baseline and cardiovascular disease (CVD) risk in 6- to 10-year-olds (cross-sectional) and 2 years later (8- to 12-year-olds [longitudinal]) and whether changes with age in CRF are associated with CVD risk in children aged 8 to 12 years. Patients and Methods Spanish primary schoolchildren (n=236) aged 6 to 10 years participated at baseline. Of the 23 participating primary schools, 22% (n=5) were private schools and 78% (n=18) were public schools. The dropout rate at 2-year follow-up was 9.7% (n=23). The 20-m shuttle run test was used to estimate CRF. The CVD risk score was computed as the mean of 5 CVD risk factor standardized scores: sum of 2 skinfolds, systolic blood pressure, insulin/glucose, triglycerides, and total cholesterol/high-density lipoprotein cholesterol. Results At baseline, CRF was inversely associated with single CVD risk factors (all P<.05) and CVD risk score at baseline and follow-up (P<.001). Cardiorespiratory fitness cutoff points of 39.0 mL/kg per minute or greater in boys and 37.5 mL/kg per minute or greater in girls are discriminative to identify CVD risk in childhood (area under the curve, >0.85; P<.001) and to predict CVD risk 2 years later (P=.004). Persistent low CRF or the decline of CRF from 6-10 to 8-12 years of age is associated with increased CVD risk at age 8 to 12 years (P<.001). Conclusion During childhood, CRF is a strong predictor of CVD risk and should be monitored to identify children with potential CVD risk.