Background We examined the association between clustering of risk factors and the risk for coronary heart disease, stroke, and all-cause mortality. Methods. Data from the First National Health and Nutrition Examination Survey Epidemiologic Follow-Up Study (N = 12,932) were used to estimate the relative risk for coronary heart disease (N = 2,255), stroke (N = 929), and death from any cause (N = 4,506) by the number of cardiovascular disease risk factors present. Risk factors included current smoking, overweight, hypertension, high blood cholesterol, and diabetes. Results. The proportions of respondents with 0, 1, 2, 3, or greater than or equal to 4 risk factors were 25.0, 32.8, 27.8, 12.3, and 2.1%, respectively. Relative risks for coronary heart disease associated with having 1, 2, 3, and greater than or equal to 4 risk factors were 1.6 (95% confidence interval [CI] 1.4, 1.9), 2.2 (95% CI 1.9, 2.6), 3.1 (95% CI 2.6, 3.6), and 5.0 (95% CI 3.9, 6.3), respectively. Relative risks for stroke associated with the same risk levels were 1.4 (95% CI 1.1, 1.8), 1.9 (95% CI 1.5, 2.4), 2.3 (95% CI 1.7, 3.0), and 4.3 (95% CI 3.0, 6.3), respectively. Similar results were observed for all-cause mortality. Conclusions. Risk for cardiovascular disease and all-cause mortality increased substantially with each additional risk factor. This supports the continued need for primary prevention of cardiovascular disease risk factors.