High dietary glycemic load (GL) has been inconsistently associated with risk of colon cancer. We analyzed data for 1093 incident cases and 1589 controls in a population-based case-control study of colon cancer to further clarify the GL-colon cancer relationship. GL was assessed using a self-administered food frequency questionnaire. Cases had a significantly higher GL intake (mean = 136.4, SD = 24.5) than controls (mean = 132.8, SD = 25.2) (P = 0.0003). In a multivariate unconditional logistic regression model, the odds ratios (ORs) for colon cancer increased significantly with increasing GL: compared to the bottom quartile of GL, the ORs (95% CI) for the 2nd through the upper quartiles were 1.38 (1.06, 1.80), 1.67 (1.30, 2.13), and 1.61 (1.25, 2.07), respectively (P trend < 0.0001). Stratified analyses showed that the association was more pronounced among older participants [ORs (95% CI) for the 2nd through the upper quartiles were 1.35 (0.91, 2.00), 1.87 (1.29, 2.71), 2.02 (1.39, 2.95), respectively] than among younger participants [ORs were 1.46 (1.02, 2.10), 1.53 (1.09, 2.15), and 1.35 (0.96, 1.91), respectively] (P int = 0.02). Our results provide support for the hypothesis that a diet with high GL increases the risk of colon cancer.