The objective of this study was to prospectively examine the comparative importance of body mass index (BMI) and metabolic syndrome (MS) related risk factors in predicting future risk of cardiovascular disease (CVD) in women. Of 25,626 women aged>or=45 years and free of CVD, cancer, and diabetes at baseline in the Women's Health Study, all women were classified into 6 groups according to 3 BMI categories (<25, 25 to 29.9, and >or=30 kg/m2) and the presence or absence of MS, defined using modified criteria of the National Cholesterol Education Program Adult Treatment Program III. During a median 10-year follow-up, 724 incident CVD events were documented. Compared with lean women without MS, multivariate relative risks of CVD, adjusting for age, physical activity, and other covariates, were 2.40 (95% confidence interval [CI] 1.71 to 3.37) for lean women who had MS, 1.08 (95% CI 0.87 to 1.33) for overweight women who had no MS, 3.01 (95% CI 2.30 to 3.94) for overweight women with MS, 1.58 (95% CI 1.21 to 2.08) for obese women without MS, and 2.89 (95% CI 2.19 to 3.80) for obese women with MS. Similar associations were evident for total coronary heart disease, but were not significant for total stroke. Overall, although C-reactive protein added additional prognostic information beyond BMI and MS, it did not fully account for the observed high risk of CVD associated with MS. In conclusion, MS may largely account for the increased risk of CVD associated with BMI in apparently healthy women.