We examined the incidence of nonfatal and fatal coronary heart disease in relation to obesity in a prospective cohort study of 115,886 U.S. women who were 30 to 55 years of age in 1976 and free of diagnosed coronary disease, stroke, and cancer. During eight years of follow-up (775,430 person-years), we identified 605 first coronary events, including 306 nonfatal myocardial infarctions, 83 deaths due to coronary heart disease, and 216 cases of confirmed angina pectoris. A higher Quetelet index (weight in kilograms divided by the square of the height in meters) was positively associated with the occurrence of each category of coronary heart disease. For increasing levels of current Quetelet index (less than 21, 21 to less than 23, 23 to less than 25, 25 to less than 29, and greater than or equal to 29), the relative risks of nonfatal myocardial infarction and fatal coronary heart disease combined, as adjusted for age and cigarette smoking, were 1.0, 1.3, 1.3, 1.8, and 3.3 (Mantel-extension chi for trend = 7.29; P less than 0.00001). As expected, control for a history of hypertension, diabetes mellitus, and hypercholesterolemia--conditions known to be biologic effects of obesity--attenuated the strength of the association. The current Quetelet index was a more important determinant of coronary risk than that at the age of 18; an intervening weight gain increased risk substantially. These prospective data emphasize the importance of obesity as a determinant of coronary heart disease in women. After control for cigarette smoking, which is essential to assess the true effects of obesity, even mild-to-moderate overweight increased the risk of coronary disease in middle-aged women.