The relationship of circulating levels of high-sensitivity C-reactive protein (CRP) with cardiovascular disease (CVD) risk, particularly with consideration of effects at intermediate levels of risk, has not been fully assessed. Among 3006 offspring participants in the Framingham Heart Study free of CVD (mean age, 46 years at baseline), there were 129 hard coronary heart disease (CHD) events and 286 total CVD events during 12 years of follow-up. Cox regression, discrimination with area under the receiver operating characteristic curve, and net reclassification improvement were used to assess the role of CRP on vascular risk. In an age-adjusted model that included both sexes, the hazard ratios for new hard CHD and total CVD were significantly associated with higher CRP levels. Similar analyses according to increasing homocysteine level showed significant protective associations for hard CHD but not for total CVD. In multivariable analyses that included age, sex, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, diabetes mellitus, current smoking, hypertension treatment, and homocysteine, the log CRP level remained significantly related to development of hard CHD and total CVD and provided moderate improvement in the discrimination of events. The net reclassification improvement when CRP was added to traditional factors was 5.6% for total CVD (P=0.014) and 11.8% for hard CHD (P=0.009). Circulating levels of CRP help to estimate risk for initial cardiovascular events and may be used most effectively in persons at intermediate risk for vascular events, offering moderate improvement in reclassification of risk.