Red cell distribution width (RDW) has emerged as a powerful predictor of all-cause mortality in variety of cardiovascular settings. However, no data are available associating RDW with coronary heart disease (CHD) risk in a healthy and nationally representative multiethnic population. A total of 7,556 participants of the National Health and Nutrition Examination Surveys 1999 to 2006 (age 41.5 ± 15.8 years, 60% women) were divided into 3 categories according to their 10-year Framingham risk of hard CHD events: <10% (n = 6,173, reference category), 10% to 20% (n = 1,093, intermediate-risk category), and >20% (n = 290, high-risk category). Unadjusted and adjusted multivariate logistic regression analyses were performed evaluating RDW as a predictor of CHD risk. Each unit increase (0.1) in RDW posed a statistically significant greater odds of being in the intermediate-risk category (odds ratio −1.35, 95% confidence interval 1.27 to 1.45, p <0.001) and high-risk category (odds ratio −1.38, 95% confidence interval 1.25 to 1.53, p <0.001) compared to the reference category, after adjusting for race, body mass index, estimated glomerular filtration rate, hemoglobin A1c, C-reactive protein, hemoglobin, and mean corpuscular volume. Additional adjustments with serum iron, vitamin B₁₂, and folic acid levels did not affect the association. Subsequently, we divided participants into 2 categories according to their anemia status (as defined by the World Health Organization) to evaluate its effect. An RDW level greater than the seventy-fifth percentile in both anemic and nonanemic participants was a significant predictor of greater CHD risk while RDW of the seventy-fifth percentile or less in anemic participants failed to predict CHD (compared to nonanemic participants with similar RDW as the reference category). In conclusion, a higher RDW appears to be a powerful independent predictor of future CHD risk.