The major known cardiovascular risk factors, age, cholesterol, blood pressure, cigarette smoking, and diabetes and family history of heart attack, explain only a proportion of cardiovascular disease. In a study of 1,491 men and 1,924 women aged 50-79 years in an upper middle-class Caucasian population in Rancho Bernardo, southern California, who were free of known cardiovascular disease at baseline in 1972-1974 and who were followed for an average of nine years, family history of stroke in any first-degree relative was an independent predictor of ischemic heart disease mortality in men 50-64 years of age (relative risk = 3.3, p less than 0.05) and of stroke mortality in women 50-79 years of age (relative risk = 2.3, p less than 0.05) after controlling for all the above risk factors. In contrast, family history of stroke was not predictive of stroke mortality in men or of ischemic heart disease mortality in women. These results suggest that family history of stroke may be used as a marker for high-risk subjects and to identify and investigate other major genetic or environmental determinants for cardiovascular disease, particularly sex differences.