OBJECTIVE: The association between body mass index (BMI) and colon cancer has been reported to be different for men and women. No prior literature has examined if estrogen influences these differences. METHODS: Using data from an incident population-based case (n = 1,972) and control (n = 2386) study of colon cancer we evaluated if estrogen modifies the association between BMI and risk of colon cancer. RESULTS: Women who were estrogen-negative (postmenopausal women not taking hormone replacement therapy, HRT) were at increased risk of colon cancer regardless of indicator of estrogen status used (i.e. estrogen-negative compared to estrogen-positive women defined as either being premenopausal or postmenopausal women using HRT, OR 1.54, 95% CI 1.23-1.93; no recent exposure to estrogens compared to current or HRT use within the past 2 years, OR 1.58, 95% CI 1.24-2.00; postmenopausal women not currently using HRT compared to postmenopausal women taking HRT, OR 1.65, 95% CI 1.29-2.12). BMI (kg/m2) was not associated with an increased risk of colon cancer among women who were estrogen-negative. However, women who were estrogen-positive experienced a greater than two-fold increase in colon cancer risk if they had a BMI of > 30 relative to those who had a BMI of <23 (for estrogen-positive, OR, 2.50, 95% CI 1.51-4.13; premenopausal, OR 2.19, 95% CI 0.94-5.07; postmenopausal using HRT, OR 3.36, 95% CI 1.58-7.13). Among men the colon cancer risk associated with BMI decreased with advancing age. Physical activity modified the increased colon cancer risk associated with a large BMI. CONCLUSIONS: These data suggest the importance of estrogen in colon cancer etiology. Being estrogen-negative resulted in a significant increased risk of colon cancer. However, BMI significantly increased the risk of colon cancer among women who were estrogen-positive. We hypothesize that estrogen up-regulates IGF-I receptors and IRS-I levels in the colon, which in turn increases susceptibility to obesity-induced increased levels of insulin. We further hypothesize that androgens may have similar effects in men given the decline in colon cancer risk associated with BMI with advancing age.