Background: The association between estimated 10-year risk for coronary heart disease (CHD) and systemic inflammation, which is a known risk factor for cardiovascular events, remain largely unknown. We sought to determine whether the distribution of the 10-year risk in a dose-dependent way is associated with novel inflammatory markers among U.S. adults. Methods: We applied the risk prediction algorithm used by the National Cholesterol Education Program Adult Treatment Panel III guidelines to data from 6,371 participants (age 40 to 79 years) without self-reported heart attack, stroke, peripheral vascular disease, and diabetes in NHANES III. Results: After adjustments for age, sex, BMI, race, and co-morbidities, participants with high risk had circulating leukocyte, platelet, fibrinogen and homocysteine levels that were 914/µL (95% confidence interval [CI], 672 to 1,156/µL), 10,222/µL (95% CI, 2,837 to 17,607/µL), 21.9 mg/dl (95% CI, 12.5 to 29.4 mg/dl) and 1.5 µmol/L (95% CI 0.8 to 2.3 µmol/L) higher, respectively, than in those with low risk. They were also more likely to have elevated levels of CRP, fibrinogen and homocysteine (Table). There were dose-dependent increases in circulating levels of markers across 3 risk groups. Conclusions: These findings indicate that low-grade systemic inflammation and hyperhomocysteinemia were present in participants with high 10-year risk for CHD. These observations may in part explain the high rates of cardiovascular events in a high-risk population.