Obesity is a risk factor for cardiovascular disease, whereas high cardiorespiratory fitness (CRF) is cardioprotective. This study evaluated the competing effect of weight and fitness on biomarkers of cardiovascular risk in a nationally representative sample of 2,112 adults (20 to 49 years of age; body mass index [BMI] > or =18.5 kg/m(2)) without previously diagnosed cardiovascular disease from the National Health and Nutrition Examination Survey 1999 to 2002. CRF levels were assigned using age- and gender-specific reference points of estimated maximal oxygen consumption calculated from submaximal graded exercise treadmill testing. CRF was also categorized by sample-specific tertiles of maximal oxygen consumption. Weight was categorized using BMI. Fasting insulin level >12.2 mU/L, C-reactive protein level > or =3.0 mg/L, and total cholesterol/high-density lipoprotein ratio (TC/HDL) >5 characterized increased cardiovascular risk. CRF and BMI were independently associated with increased fasting insulin and C-reactive protein (p <0.05). When patients with low, moderate, and high CRF were further stratified as normal, overweight, or obese, weight remained significantly associated with increased fasting insulin, C-reactive protein, and TC/HDL (p <0.001), but CRF did not. Logistic regressions evaluating increased fasting insulin, C-reactive protein, and TC/HDL demonstrated no significant differences in overweight/obese patients by CRF level after adjustment for other factors. Significant differences were present between normal-weight and overweight or obese patients regardless of fitness level. Analyses using tertiles of CRF yielded similar results. In conclusion, patients who are "fat but fit" require weight-loss interventions to improve their cardiovascular risk profiles. Future interventions should emphasize weight control, even for those with high CRF.