Meat consumption may especially increase risk of colon cancer when the meat is prepared at high temperatures and consumed by subjects with an inherited susceptibility to well-done meat. In this United States case-control study, the association between meat consumption, genetic susceptibility, and colon cancer risk was studied. Meat consumption data were available from a detailed diet history questionnaire and from questions about methods of preparation. Molecular variants in the carcinogen-metabolizing genes NAT2 and GSTM1 were determined in DNA extracted from WBCs. A total of 1542 cases and 1860 population-based controls were included in these analyses. The amount of red and white meat consumed was not associated with overall colon cancer risk. Processed meat consumption was weakly positively associated with colon cancer risk in men only (odds ratio for highest versus lowest quintile of intake = 1.4, 95% confidence interval = 1.0-1.9). The frequency of fried, broiled, baked, or barbecued meat, use of drippings, and doneness of meat were not significantly associated with risk. The Mutagen Index, as an estimate for exposure to mutagenic or carcinogenic substances, was slightly positively associated with colon cancer risk in men (odds ratio = 1.3, 95% confidence interval = 1.0-1.7). No significant associations with colon cancer risk were observed for different NAT2 and GSTM1 gene variants. The observed associations with processed meat and the Mutagen Index were strongest for those with the intermediate or rapid NAT2 acetylator phenotype. Associations were not markedly influenced by lack of the GSTM1 gene. This study provides little support for an association between meat consumption and colon cancer risk but does provide some, albeit not strong, evidence for a modifying effect of molecular variants of the NAT2 gene.