Mutation of the adenomatous polyposis coli (APC) tumor suppressor gene is an important initiating factor in the early stages of the adenoma-carcinoma sequence. The aim of this study was to investigate the two most common APC variants (Asp1822Val and Gly2502Ser) and their association with colorectal cancer and adenoma and whether these relationships are influenced by dietary and lifestyle factors. We analyzed 556 adenoma cases and 557 matched controls and 197 cancer cases and 490 matched controls nested within the Nurses' Health Study cohort, 274 cancer cases and 456 matched controls nested within the Physicians' Health Study cohort, and 375 adenoma cases and 724 matched controls nested within the Health Professionals Follow-up Study cohort. APC Asp1822Val and Gly2502Ser polymorphisms were not associated with risk of colorectal cancer or adenoma. For colorectal cancer, a significant interaction was found between Asp1822Val genotype and postmenopausal hormone (PMH) use among postmenopausal women (P(interaction) = 0.03). Current PMH use was associated with reduced risk overall and a statistically significant lower risk of colorectal cancer among carriers of one or two copies of the APC 1822Val allele (relative risk, 0.46; 95% confidence interval, 0.24-0.88) relative to wild-type never or past PMH users. Our results suggest that cigarette smoking, alcohol intake, and family history of colorectal cancer were positively associated and regular aspirin intake was inversely associated with colorectal adenoma in men and women. No gene-environment interactions were observed with these risk factors or with other dietary risk factors previously hypothesized to interact with the APC Asp1822Val polymorphism.