Overweight and obesity have been prospectively associated with the risk of coronary heart disease (CHD). Less clear is the relation of excess weight to risk of CHD among men and women with comorbid conditions, and the proportion of CHD risk attributable to excess weight in the US population. To assess the risk of CHD associated with excess weight among men and women with and without associated comorbid conditions, and determine the population attributable risk of CHD associated with excess weight. The study population consisted of two prospective cohorts, the Health Professionals Follow-up Study (HPFS) (N = 42,351 men; age range at baseline, 39-75 years) and the Nurses' Health Study (NHS) (N = 76,703 women; age range at baseline, 39-65 years). A total of 2,771 incident cases of CHD among the men and 2,359 among the women were documented over the 16 years of follow-up. Overall, the relative risk (RR) of CHD associated with BMI > or =30 kg/m(2) compared with BMI 18.5-22.9 kg/m(2) was 2.13 (95% confidence interval (CI), 1.82-2.48) among the men and 2.48 (95% CI, 2.20-2.80) among the women. The risk of CHD increased with BMI, both with and without the presence of comorbid conditions. Our estimates suggest that more than a third of all incident CHD in US men and women may be attributed to excess weight. Excess weight is associated with increased risk of CHD among men and women, both alone and in combination with comorbid conditions, though the results require careful interpretation. A substantial proportion of incident CHD may be attributed to excess weight.