The association of meat intake and meat-derived mutagens with colorectal tumor risk remains unclear. We evaluated this hypothesis in a large colonoscopy-based case-control study. Included in the study were 2,543 patients with polyp [(1,881 with adenomas and 622 with hyperplastic polyp (HPP)] and 3,764 polyp-free controls. Surveys obtained information about meat intake by cooking methods and doneness levels plus other suspected or known risk factors for colorectal tumors. Unconditional logistic regression was used to derive ORs after adjusting for potential confounders. High intake of red meat and processed meat (P(trend) < 0.05), particularly red meat cooked using high-temperature cooking methods (P(trend) ≤ 0.01), was associated with an elevated risk for colorectal polyps. A significant positive association between exposures to meat-derived heterocyclic amines (HCA) and risk of polyps was found for both adenomas and HPPs. Furthermore, the positive association with red meat intake and HCA exposure was stronger for multiple adenomas than for single adenoma as well as for serrated than for nonserrated adenomas. This study supports a role for red meat and meat-derived mutagen exposure in the development of colorectal tumor.