Background: Recent evidence implicates inflammation in the pathogenesis of coronary heart disease (CHD). C-reactive protein, a plasma marker of inflammation, is a marker of CHD risk but has been studied in few prospective investigations of the general population. Methods and Results: We prospectively examined the association of CRP with incident CHD among middle-aged adults in the Atherosclerosis Risk In Communities (ARIC) study. With the use of a nested case-cohort approach, we measured CRP in stored, baseline blood samples of 2 groups of subjects in whom CHD developed during follow-up (242 incident cases from 1987 to 1993 and 373 from 1990 to 1995) and, for comparison, 2 stratified random samples of noncases. In analyses adjusted for demographic variables and traditional CHD risk factors, the relative risk of CHD across quintiles of CRP was 1.0, 0.8, 1.6, 1.9, and 1.5 for events from 1987 to 1995 (P for trend = .01). As expected, inclusion of fibrinogen, intracellular adhesion molecule-1, and white blood cell count (other potential markers of the inflammatory reaction) attenuated the association of CRP with CHD incidence. In a supplemental cross-sectional analysis, CRP was not associated with carotid intima-media thickness after adjustment for major risk factors. Conclusions: C-reactive protein is a moderately strong marker of risk of CHD in this cohort of middle-aged adults, consistent with the role of inflammation in the pathogenesis of CHD events. The association was not specific to CRP because other markers of inflammation could largely account for the finding.