Most colorectal cancers arise from adenomatous polyps or certain hyperplastic polyps. Only a few studies have investigated potential genetic modifiers of the associations between meat intake and polyp risk, and results are inconsistent. Using data from the Tennessee Colorectal Polyp Study, a large colonoscopy-based study, including 1,002 polyp cases (557 adenoma only, 250 hyperplastic polyp only, 195 both polyps) and 1,493 polyp-free patients, we evaluated the association of colorectal polyp risk with carcinogen exposure from meat and genetic polymorphisms in enzymes involved in heterocyclic amine (HCA) metabolism, including N-acetyltransferase 1 (NAT1) and N-acetyltransferase 2 (NAT2), cytochrome P450 1A2 (CYP1A2), and aryl hydrocarbon receptor (AhR). Data on intake levels of meats by preparation methods, doneness preferences, and other lifestyle factors were obtained. Fourteen single nucleotide polymorphisms in the AhR, CYP1A2, NAT1, and NAT2 genes were evaluated. No clear association was found for any polymorphisms with polyp risk. However, apparent interactions were found for intake of meat and HCAs with AhR, NAT1, and NAT2 genotypes, and the interactions were statistically significant for the group with both adenomatous and hyperplastic polyps. Dose-response relationships with meat or HCA intake were found only among those with the AhR GA/AA (rs2066853) genotype, NAT1 rapid, or NAT2 rapid/intermediate acetylators but not among those with other genotypes of these genes. This dose-response relationship was more evident among those with both AhR GA/AA and the NAT1 rapid acetylator than those without this genotype combination. These results provide strong evidence for a modifying effect of metabolizing genes on the association of meat intake and HCA exposure with colorectal polyp risk.