We sought to study relationship between cardiorespiratory fitness and C-reactive protein (CRP) in subjects with the metabolic syndrome. Recent studies have shown an association between the metabolic syndrome and chronic subclinical inflammation, as determined by elevated CRP. Cardiorespiratory fitness is associated with a lower risk of diabetes and improved insulin resistance. Physical fitness was assessed in 1,640 subjects using the Bruce treadmill protocol and expressed as maximal metabolic equivalents. The level of CRP was measured using a high-sensitivity assay. Geometric mean CRP was calculated across quartiles of fitness after adjustment for age, gender, smoking, use of medications, and coronary disease. A strong inverse trend toward decreasing CRP levels with increasing fitness quartiles was present in subjects without metabolic abnormalities, subjects with one or two metabolic abnormalities, and subjects with the metabolic syndrome (all p <or= 0.001). The effect of fitness was particularly robust among subjects with the metabolic syndrome. The adjusted mean CRP in subjects in the upper and lower fitness quartiles was 1.48 versus 0.93 mg/dl in subjects without metabolic abnormalities, 2.40 versus 1.66 mg/dl in subjects with one or two metabolic abnormalities, and 4.62 versus 2.20 mg/l in subjects with the metabolic syndrome (p = 0.049 for the interaction between fitness and number of metabolic abnormalities). Subjects with the metabolic syndrome who maintain a high fitness level have markedly lower CRP concentrations, as compared with those with a low fitness level.