Hyperinsulinemia may explain excess colorectal cancer among individuals who are overweight or inactive. Recent studies have observed elevated colorectal cancer risk among individuals with elevated insulin levels 2 hours after oral glucose challenge or with elevated plasma C-peptide levels. The effect of consuming a high glycemic diet on colorectal risk, however, remains uncertain. Two prospective cohort studies, the Nurses' Health Study and the Health Professionals Follow-up Study, contributed up to 20 years of follow-up. After exclusions, 1,809 incident colorectal cancers were available for analyses. Dietary glycemic load (GL) was calculated as a function of glycemic index (postprandial blood glucose response as compared with a reference food), carbohydrate content, and frequency of intake of individual foods reported on food frequency questionnaires. Multivariable Cox proportional hazards models were used to adjust for potential confounders. Intakes of dietary carbohydrate, GL, overall glycemic index, sucrose, and fructose were not associated with colorectal cancer risk in women. A small increase in risk was observed in men with high dietary GL (multivariate relative risk, 1.32; 95% confidence interval, 0.98-1.79; highest versus lowest quintile), sucrose or fructose (multivariate relative risk, 1.37; 95% confidence interval, 1.05-1.78; highest versus lowest quintile of fructose, P = 0.008). Associations were slightly stronger among men with elevated body mass index (> or =25 kg/m(2)). Results among women were similar after stratifying by body mass index or physical activity. High intakes of GL, fructose, and sucrose were related to an elevated colorectal cancer risk among men. For women, however, these factors did not seem to increase the risk of colorectal cancer.