Purpose: The relationship of both physical activity and predicted maximum oxygen consumption ((V) over dot O-2max) with the clustering of metabolic risk factors associated with the metabolic syndrome (MS) was examined within 711 employed middle-aged (46.9 +/- 7.8 yr) men. Methods: Metabolic markers included fasting glucose, triglycerides, high-density lipoprotein cholesterol, blood pressure, and BMI, defined by highest risk quintiles or clinically relevant risk thresholds. Results: The prevalence and age-adjusted odds ratios of all MS clusters were inversely graded across both higher physical activity index (PAT) and cardiorespiratory fitness (CRF) categories. The age-adjusted odds ratio for the clustering of clinically relevant metabolic markers was 0.60 (95% CI 0.22-1.22) for subjects in the occasional/light PAI, 0.32 (95% CI 0.12-0.82) for the moderate/moderately vigorous PAI, and 0.13 (95% CI 0.02-1.02) for the vigorous PAI when compared with subjects in the sedentary PAI (P < 0.05 for trend). The corresponding age-adjusted odds ratio was 0.28 (95% CI 0.14-0.57) for subjects in the moderate fitness category and 0.12 (95% CI 0.05-0.32) for the highest fitness category compared with those in the lowest fitness category (P < 0.001 for trend). Higher levels of physical activity or CRF were also associated with significantly lower age-adjusted odds ratios for the MS after exclusion of obesity in the MS definition. Conclusion: Overall, these cross-sectional results suggest that higher physical activity and predicted (V) over dot O-2max levels are associated with a decreased clustering of risk factors associated with the MS in middle-aged men of higher social class.