Objectives: The goal of this work was to assess whether high dietary glycemic load and glycemic index are associated with an increased risk of cardiovascular disease (CVD). Background: The associations of dietary glycemic index and glycemic load with risk of CVD are not well established, particularly in populations consuming modest glycemic load diets. Moreover, risk may differ between lean and overweight subjects. Methods: Associations of glycemic index and glycemic load with incident CVD were examined in a prospective cohort of 15,714 Dutch women age 49 to 70 years without diabetes or CVD. Dietary glycemic index and glycemic load were calculated using the glycemic index, carbohydrate content, and frequency of intake of individual foods. Results: During 9 ± 2 years of follow-up, 556 cases of coronary heart disease (CHD) and 243 cases of cerebrovascular accident (CVA) occurred. Dietary glycemic load (mean = 100; SD = 17) was associated with increased risk of CVD, adjusted for CVD risk factors and dietary variables, with a hazard ratio (HR) for the highest against lowest quartile of 1.47 (95% confidence interval [CI] 1.04 to 2.09; ptrend = 0.03). Similar results were observed for dietary glycemic index with a corresponding HR of 1.33 (95% CI 1.07 to 1.67; ptrend = 0.02). Glycemic load tended to be associated with both CHD (HR 1.44; 95% CI 0.95 to 2.19; ptrend = 0.14) and CVA (HR 1.55; 95% CI 0.81 to 2.97; ptrend = 0.10), but glycemic index only with CHD (HR 1.44; 95% CI 1.10 to 1.89; ptrend = 0.01). Among overweight women (body mass index >25 kg/m2), glycemic load was associated with CVD (1.78; 95% CI 1.11 to 2.85; ptrend = 0.04), but not among normal weight women (pinteraction = 0.19). Body mass index did not modify the association of glycemic index with CVD. Conclusions: Among women consuming modest glycemic load diets, high dietary glycemic load and glycemic index increase the risk of CVD, particularly for overweight women.