Epidemiological studies report that high sucrose consumption is associated with increased risk of colon cancer. One hypothesis is that this association is mediated by elevated circulatory insulin and IGF levels promoting intestinal proliferation. To test this hypothesis, APC(Min) mice and their wild type littermates were fed, starting at 4 wk of age, sucrose or cornstarch as the sole carbohydrate source in the absence or presence of low levels of dietary sulindac for 10 or 16 wk, respectively. APC(Min) mice fed sucrose had an increased tumor number in the proximal third of the small intestine in both studies and a higher incidence of papillary colon tumors in the 16-wk feeding study (P < or = 0.05). Mice fed sucrose (relative to cornstarch) had higher body weights and greater Ki67-labeling indexes in colonic epithelium than mice fed cornstarch in both feeding studies (P < or = 0.05). Furthermore, mice fed sucrose had higher serum glucose and liver IGF-I mRNA concentrations (P < or = 0.05) and tended to have higher serum insulin levels (P = 0.08). These results support the hypothesis that high dietary sucrose intake promotes intestinal proliferation and tumorigenesis by increasing circulating levels of insulin and IGF-I.