Technical Abstract: The purpose of this study was to examine whether cardio metabolic risk factors are predicted by fitness or fatness among adolescents. Participants are 4955 (2614 female) 6th grade students with complete data from 42 US middle schools. Fasting blood samples were analyzed for total cholesterol, high density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol, triglyceride, glucose and insulin concentrations. Waist circumference and blood pressure were assessed. Body mass index (BMI) was categorized as normal weight, overweight or obese as a measure of fatness. Fitness was assessed using the multi-stage shuttle test and converted into gender specific quintiles. Gender-specific regression models, adjusted for race, pubertal status, and household education, were run to identify whether BMI-group predicted risk factors. Models were repeated with fitness group and both fitness and fatness groups as predictors. Results show that means for each risk factor (except HDL, which was the reverse) were significantly higher (p<.0001) with increased fatness, and differed across all BMI groups (p<.001). Waist circumference, LDL cholesterol, triglycerides, diastolic blood pressure and insulin were inversely associated with fitness (p<.001). When both fatness and fitness were included in the model, BMI was associated (p<.001) with almost all cardio metabolic risk factors; fitness was only associated with waist circumference (both genders), LDL cholesterol (males), and insulin (both genders). Other associations between fitness and cardio metabolic risk factors were attenuated after adjustment for BMI group. Both fatness and fitness are associated with cardio metabolic risk factors among 6th grade youth, but stronger associations were observed for fatness. While maintaining high levels of fitness and preventing obesity may positively affect cardio metabolic risk factors, greater benefit may be obtained from obesity prevention.