Abstract Background: Circulating insulin levels have been positively associated with risk of colorectal cancer; however, it remains unclear whether a diet inducing an elevated insulin response influences colorectal cancer risk. On the basis of a novel insulin index for individual foods, we estimated insulin demand for overall diets and assessed its association with colorectal cancer in the Nurses' Health Study and Health Professionals Follow-up Study. Methods: We followed 86,740 women and 46,146 men who were free of cancer and diabetes at baseline and identified a total of 2,481 colorectal cancer cases during up to 26 years of follow-up. Dietary insulin load was calculated as a function of food insulin index and the energy content of individual foods was reported on food frequency questionnaires. Average dietary insulin index was calculated by dividing the dietary insulin load by the total energy intake. Results: Dietary insulin load and dietary insulin index were not associated with risk of colorectal cancer. Comparing the highest with the lowest quintiles, the pooled multivariate relative risks of colorectal cancer were 0.91 (95% CI = 0.79–1.05) for dietary insulin load and 0.93 (95% CI = 0.81–1.08) for dietary insulin index. Body mass index and physical activity did not modify the association of dietary insulin load or index with colorectal cancer. Conclusion: A diet high in foods that increase postprandial insulin levels did not increase the risk of colorectal cancer in this large prospective study. Impact: This study is the first to investigate insulin index and load in relation to colorectal cancer. Cancer Epidemiol Biomarkers Prev; 19(12); 3020–6. ©2010 AACR.