Since hyperinsulinemia is implicated in the development of colorectal cancer, determinants of serum insulin levels, like the glycemic load and the glycemic index of the diet, could influence cancer risk. Our objective was to evaluate whether a diet with a high glycemic load or glycemic index is associated with increased colorectal cancer risk. In the Netherlands Cohort Study, 120,852 subjects completed a food frequency questionnaire in 1986. After 11.3 years of follow-up, 1,225 colon and 418 rectal cancer cases were available for analysis. A case-cohort approach was used to estimate multivariate adjusted rate ratios and 95% confidence intervals for quintiles of energy-adjusted glycemic load and glycemic index. The RR for colorectal cancer comparing the highest versus the lowest quintile levels of glycemic load and glycemic index were 0.83 (95% CI: 0.64-1.08) and 0.81 (95% CI: 0.61-1.08) for men and 1.00 (95% CI: 0.73-1.36) and 1.20 (95% CI: 0.85-1.67) for women. In general, no clear associations with cancer subsites were observed. Glycemic load and glycemic index were borderline significantly associated with an increased risk of proximal colon cancer in women (p-trend = 0.06 and 0.08, respectively), however, these associations were attenuated after exclusion of the first 2 years of follow-up (p-trend = 0.165 and 0.254, respectively). In men, glycemic index was associated with a reduced risk of distal colon cancer (p-trend = 0.03). Overall, our findings do not support the hypothesis that a diet with a high glycemic load or index is associated with a higher risk of colorectal cancer. © 2007 Wiley-Liss, Inc.