We examined the extent of coronary heart disease (CHD) risk factor clustering in overweight persons with a body mass index (BMI) of 25 to 29 and an obesity BMI of >/=30 and the influence of this on the hazard of myocardial infarction and coronary mortality. A total of 1,309 men and 739 women aged 30 to 74 years, initially free of cardiovascular disease, comprised the overweight subject group, and 375 men and 356 women comprised the obese subject group at risk. The sample was derived from the original Framingham Study cohort at the 11th biennial examination, and their offspring at initial examination. During 16 years of follow-up of overweight subjects, 188 men and 44 women had CHD events, indicating an age-adjusted rate that was not much different from the slim subjects. In the obese subject group, 72 men and 37 women developed CHD, corresponding to age-adjusted risk ratios 1.48 times that of lean men, and 2.09 times that of lean women. Risk factors were categorized as systolic blood pressure >/=140 mm Hg, total cholesterol >/=240 mg/dl, high-density lipoprotein (HDL) cholesterol <35 mg/dl for men and <40 mg/dl for women, heart rate >80 beats/min, history of smoking, history of type 2 diabetes, and electrocardiographic left ventricular hypertrophy. Being overweight occurred in isolation of CHD risk factors in 22% of men and in 16.4% of women. Being obese occurred in isolation in only 12.8% of men and 9% of women. Clusters of >/=2 risk factors occurred in 56% of obese men and in 62.4% of obese women, a frequency substantially exceeding that in slim subjects. Compared with obese men without risk factors, those with >/=3 factors had a 2.07 age-adjusted relative risk of developing CHD, and obese women had a 10.9 relative risk (p <0.05). Being overweight and obese promotes clusters of CHD risk factors that greatly influence their impact. Global risk assessment can identify high-risk overweight candidates for CHD who most urgently need correction of associated risk factors, as well as sustained weight reduction.