Introduction: Physical fitness has a protective effect with regard to the risk of developing coronary disease or diabetes. C-reactive protein (CRP) levels are directly related to increased risk of coronary disease and diabetes. However, data on the association between physical fitness and CRP are sparse. Methods: Physical fitness was assessed in a population-based cross-sectional study (n = 892; age 50 +/- 9 years) using the Bruce treadmill protocol. CRP was measured using a high-sensitivity assay. Results: Geometric mean CRP levels were calculated across quartiles of physical fitness after adjustment for age, gender, body mass index, smoking habit, presence of diabetes and hypertension, HDL cholesterol and triglyceride levels, and use of hormone replacement therapy, statins, and aspirin. CRP levels decreased with increasing quartiles of fitness (P for trend <0.0001). When used as a continuous variable in a stepwise linear regression model, the geometric mean of CRP decreased by 0.061mg/L (95% confidence interval (CI) 0.034-0.089mg/L) for each 1 unit increase in metabolic equivalents (METs). Multivariate logistic regression models showed that compared to subjects in the lowest fitness quintile, subjects in the highest fitness quintile had significantly lower adjusted odds of having a high-risk (>3mg/L) CRP level (OR 0.53; 95% CI 0.39-0.71, P = 0.007). Conclusion: CRP concentration decreases continuously with increasing levels of physical fitness. The health-related salutary effects of physical fitness may be mediated, in part, through an antiinflammatory mechanism.