It has been hypothesized that levels of triglycerides, glucose, and insulin are associated with risk of colon cancer and that diets high in simple sugars increase risk of colon cancer because of their impact on these factors. Limited epidemiological evidence supports the association between simple carbohydrates and risk of colon cancer. Using data from a population-based case-control study (n = 1993 cases and 2410 controls), we examined the associations between dietary sugars, foods containing high level of sugars, and dietary glycemic index (GI) and colon cancer. A dietary GI was developed to estimate metabolic response to a diet that may increase plasma glucose levels. Dietary data were obtained using a validated diet history questionnaire. High levels of sucrose intake were associated with increased risk of colon cancer among younger men [odds ratio (OR) for highest quintile relative to lowest, 1.59; 95% confidence interval (CI), 1.07-2.37]. There was also a trend of increasing colon cancer risk associated with a higher sucrose:dietary ratio for proximal tumors in both men and women. Individuals with proximal tumors who consumed a diet ranked as having a high GI were at increased risk (for men, comparing highest quintile to lowest quintile: OR, 1.58; 95% CI, 1.06-2.36; P trend 0.04; for women: OR, 1.72; 95% CI, 1.11-2.67; P trend 0.04). Those at greatest risk from a high dietary GI were those who were sedentary (for men, relative to those who were most active and had a low-GI diet: OR, 3.46; 95% CI, 1.78-6.70; for women: OR, 2.00; 95% CI, 0.98-4.07). We also observed that people who had a high sucrose: dietary fiber ration and who also were sedentary and had a large body mass index were at increased risk (OR, 4.58; 95% CI, 2.33-8.98) relative to those who had a low sucrose:dietary fiber ratio, were active, and had low body mass indices. These findings support previous reports that dietary sugars, especially diet high in simple carbohydrates relative to complex carbohydrates, increase risk of colon cancer, possibly through their impact on plasma glucose levels.