The peroxisome proliferator-activated receptor gamma (PPARgamma) is one of a group of ligand-activated nuclear receptors responsible for regulation of glucose, lipid homeostasis, cell differentiation, and apoptosis. The 12 proline-to-alanine (Pro12Ala) substitution polymorphism in PPARgamma produces proteins with lower activity. Variation in PPARgamma expression in the bowel and the role of dietary fatty acids as ligands for PPARgamma led investigation of whether the associations of diet with colon and rectal cancer risk were modified by PPARgamma genotype. Data (diet, lifestyle, and DNA) came from case-control studies of colon (1,577 cases and 1,971 controls) and rectal cancer (794 cases and 1,001 controls) conducted in Northern California, Utah, and the Twin City, Minnesota Metropolitan area (colon cancer study only). Unconditional logistic regression models were adjusted for age at selection, body mass index, physical activity, energy intake, dietary fiber, and calcium. We found no significant interactions between macronutrient (fat, protein, and carbohydrate) and colorectal cancer. High lutein intake [odds ratio (OR), 0.63; 95% confidence interval (95% CI), 0.44-0.89], low refined grain intake (OR, 0.70; 95% CI, 0.53-0.94), or a high prudent diet score (OR, 0.66; 95% CI, 0.49-0.89) and PA/AA PPARgamma genotype were associated with reduced colon cancer risk. Risk of rectal cancer was increased among those with the PA/AA PPARgamma genotype and a high mutagen index (OR, 1.63; 95% CI, 1.12, 2.36). Its unclear whether the alterations in risk in those with the less active phenotype for PPARgamma is related to activation of PPARgamma by nutrients or dietary patterns acting as ligands or direct influences of these nutrients on colon and rectal cancer processes that are important with lower PPARgamma activity.