Background : A high-fat diet has been recognized for some time as a major risk factor for colorectal cancer. It is thought that fat promotes this disease by increasing the levels of fatty and bile acids within the colon. These acids irritate and damage the epithelial cells of the colon. As a result of this cellular destruction, an increase in the rate of cellular proliferation occurs. Oral calcium supplementation has been proposed as a dietary intervention for individuals at high risk of colorectal cancer because of its ability to reduce rectal epithelial cell proliferation through the binding of fatty and bile acids. Placebo-controlled studies, however, have yielded varying results. Purpose : We conducted a randomized, double-blinded, placebo-controlled trial to test oral calcium supplementation in patients at high risk of developing hereditary nonpolyposis colorectal cancer. Methods : Thirty subjects at risk for this cancer, with an increased epithelial cell proliferation along the colon and rectum, were randomly assigned to either a placebo group (n = 15) or a treatment group (n = 15). They received either oral calcium carbonate (CaCO 3 ) supplements (1.5 g) or placebo (cellulose and starch) three times a day during a 12-week period. Colonic biopsy specimens (rectal, sigmoidal, and descending) were obtained prior to and after the intervention trial, during endoscopy, for determination of labeling index (LI) of whole crypts and crypt compartments by 5-bromo-2'-deoxyuridine incorporation and immunohistochemistry. Proportional bile acid compositions in duodenal bile and cytolytic activity of fecal water were also determined. All P values represent two-tailed tests of statistical significance. Results : Statistically significant reductions, comparing before with after intervention, in rectal wholecrypt LI after receiving either calcium supplements (from 10.9% ± 5.2% [mean ±SD] to 6.2% ± 1.5%; P <.02) or placebo (from 11.7% ± 4.7% to 8.2% ± 3.1% P <.05) were observed. In the three bowel segments, no statistically significant differences were observed between the supplemental calcium and placebo groups. A statistically significant reduction in cytolytic activity was determined during calcium supplementation (from 57% ± 41% to 32% ± 30%; P <.05), whereas in the placebo group, it did not change (from 42% ± 41% to 36% ± 27%; P >.10). Conclusions : Oral calcium supplementation was shown to cause only a minor nonstatistically significant reduction of epithelial cell proliferation in the rectum, compared with placebo, and to have no effect on the same parameter in the sigmoid and descending colon in first-degree relatives of hereditary nonpolyposis colorectal cancer patients. Implication : These results cast doubt on the value of calcium supplementation in the prevention of colorectal cancer, especially in individuals already consuming an adequate amount of dietary calcium. [J Natl Cancer Inst 87:598-603, 1995]