Family history of CAD, defined as parental death by CAD, was found to be a significant independent predictor of CAD in a logistic regression model controlling for standard risk factors and length of follow-up among the 5209 participants in the Framingham Study. Persons with a positive parental history have a 29% increased risk of CAD, and the strength of the association between parental history and CAD is similar to that found for other standard risk factors such as systolic blood pressure, cholesterol level, and cigarette smoking. No evidence was found that persons with a family history of CAD have a decreased capacity to cope with the deleterious effects of known risk factors; that is, no significant interaction was found between any of the risk factors and parental history of CAD. Among men with low risk for CAD by risk-factor profile (i.e., nonsmoking, thin, nonhypertensive persons), more than two thirds of those who experience CAD have a positive parental history. This study suggests that CAD among persons who are predicted to be at low risk by standard risk factors may have a substantial genetic component and that the risk associated with parental history may not be reduced by modification of these factors. Nevertheless, among persons with a positive family history, those with a favorable risk profile are at substantially less risk for CAD than those with an unfavorable risk profile.