Low intake of folate and methionine and heavy alcohol consumption have been associated with an increased overall risk of colon cancer, possibly related to their role in methylation pathways. We estimated the relative risk (RR) of colon cancer according to a history of colorectal cancer in a first-degree relative and categories of folate, methionine, and alcohol intake in a prospective cohort study of 88,758 women who completed family history and detailed food frequency questionnaires. During 16 years of follow-up, colon cancer was diagnosed in 535 women. The inverse association of folic acid with colon cancer risk was greater in women with a family history. Compared with women who consumed 200 microg or less of folic acid/day, the age-adjusted RR of colon cancer for those who consumed >400 microg/day was 0.81 (95% confidence interval, 0.62-1.07) in women without a family history of colorectal cancer and 0.48 (95% confidence interval, 0.28-0.83) in women with a family history (P for interaction = 0.02). The influence of family history was markedly diminished by use of multivitamins containing folic acid (P for interaction = 0.04). High levels of dietary methionine also reduced the effect of family history (P for interaction = 0.05), whereas moderate to heavy alcohol consumption increased the risk associated with family history (P for interaction = 0.004). Other risk factors for colorectal cancer did not significantly modify the influence of family history. Our results suggest that higher intake of folate and methionine, regular use of multivitamins containing folate, and avoidance of moderate to heavy alcohol consumption may diminish the excess risk of colon cancer associated with a family history of the disease.