Background: C-reactive protein (CRP) may help to refine global risk assessment for coronary heart disease (CHD), particularly among persons who are at intermediate risk on the basis of traditional risk factors alone. Purpose: To assist the U.S. Preventive Services Task Force (USPSTF) in determining whether CRP should be incorporated into guidelines for CHD risk assessment. Data Sources: MEDLINE search of English-language articles (1966 to November 2007), supplemented by reference lists of reviews, pertinent studies, editorials, and Web sites and by expert suggestions. Study Selection: Prospective cohort, case–cohort, and nested case–control studies relevant to the independent predictive ability of CRP when used in intermediate-risk persons. Data Extraction: Included studies were reviewed according to predefined criteria, and the quality of each study was rated. Data Synthesis: The validity of the body of evidence and the net benefit or harm of using CRP for CHD risk assessment were evaluated. The combined magnitude of effect was determined by meta-analysis. The body of evidence is of good quality, consistency, and applicability. For good studies that adjusted for all Framingham risk variables, the summary estimate of relative risk for incident CHD was 1.58 (95% CI, 1.37 to 1.83) for CRP levels greater than 3.0 mg/L compared with levels less than 1.0 mg/L. Analyses from 4 large cohorts were consistent in finding evidence that including CRP improves risk stratification among initially intermediate-risk persons. C-reactive protein has desirable test characteristics, and good data exist on the prevalence of elevated CRP levels in intermediate-risk persons. Limited evidence links changes in CRP level to primary prevention of CHD events. Limitations: Study methods for measuring Framingham risk variables and other covariates varied. Ethnic and racial minority populations were poorly represented in most studies, limiting generalizability. Few studies directly assessed the effect of CRP on risk reclassification in intermediate-risk persons. Conclusion: Strong evidence indicates that CRP is associated with CHD events. Moderate, consistent evidence suggests that adding CRP to risk prediction models among initially intermediate-risk persons improves risk stratification. However, sufficient evidence that reducing CRP levels prevents CHD events is lacking.