Context: A frequently cited concept is that individual major risk factors for coronary heart disease (CHD) are absent in many patients (perhaps > 50%) with CHD. However, prior studies have not systematically evaluated the extent to which CHD patients have previous exposure to at least 1 risk factor, including diabetes, cigarette smoking, or clinically elevated levels of cholesterol or blood pressure. Objective: To determine the frequency of exposure to major CHD risk factors. Design, Setting, and Participants: Three prospective cohort studies were included: the Chicago Heart Association Detection Project in Industry, with a population sample of 35642 employed men and women aged 18 to 59 years; screenees for the Multiple Risk Factor Intervention Trial, including 347978 men aged 35 to 57 years; and a population-based sample of 3295 men and women aged 34 to 59 years from the Framingham Heart Study (FHS). Follow-up lasted 21 to 30 years across the studies. Main Outcome Measures: Fatal CHD in all cohorts and nonfatal myocardial infarction (MI) in the FHS, compared by exposure to major CHD risk factors, defined as total cholesterol of at least 240 mg/dL (≥6.22 mmol/L), systolic blood pressure of at least 140 mm Hg, diastolic blood pressure of at least 90 mm Hg, cigarette smoking, and diabetes. Participants were stratified by sex and age (18-39 vs 40-59 years). Results: For fatal CHD (n=20995), exposure to at least 1 clinically elevated major risk factor ranged from 87% to 100%. Among those aged 40 to 59 years at baseline with fatal CHD (n=19263), exposure to at least 1 major risk factor ranged from 87% to 94%. For nonfatal MI, prior exposure was documented in 92% (95% Cl, 87%-96%) (n=167) of men aged 40 to 59 years at baseline and in 87% (95% Cl, 80%-94%) (n=94) of women in this age group. Conclusions: Antecedent major CHD risk factor exposures were very common among those who developed CHD, emphasizing the importance of considering all major risk factors in determining CHD risk estimation and in attempting to prevent clinical CHD. These results challenge claims that CHD events commonly occur in persons without exposure to at least 1 major CHD risk factor.