Background:The results of several recent epidemiologic studies suggest that estrogen replacement therapy (ERT) in postmenopausal women may decrease their risk of subsequently developing colon or colorectal cancer. However, the association is not clear, as other similar studies have failed to show this inverse relationship. Purpose: The present study attempts a more definitive analysis of the relationship between fatal colon cancer and use of ERT among women in a large prospective study of adults in the United States.Methods:Women were selected for study from the 676526 female participants in Cancer Prevention Study II (CPS-II), a prospective mortality study of about 1.2 million American men and women (from all 50 states, the District of Columbia, and Puerto Rico), begun by the American Cancer Society in 1982. The median age of the female CPS-II Participants was 56 years in 1982. Vital status was determined through December 31, 1989; 630585 participants (93.2%) were still alive and 43862 (6.5%) had died after 7 years of follow-up. Death certificates were obtained for 96.2% of participants known to have died. At the end of follow-up, 897 colon cancer deaths were observed in a cohort of 422373 postmenopausal women who were cancer free at study entry. Cox proportional hazards modeling was used to compute rate ratios (RRs) and to adjust for other potential risk factors. The likelihood ratio test (two-sided) was used to determine the statistical significance of the interaction terms.Results:Ever use of ERT was associated with significantly decreased risk of fatal colon cancer (RR = 0.71; 95% confidence interval (CI) = 0.61–0.83). The reduction in risk was strongest among current users (RR = 0.55; 95% CI = 0.40–0.76), and there was a significant (P =.0001) trend of decreasing risk with increasing years of use among all users: Users of 1 year or less had an RR of 0.81 (95% CI = 0.63–1.03), while users of 11 years or more had an RR of 0.54 (95% CI = 0.39–0.76). These associations were not altered in multivariate analyses controlling for other risk factors.Conclusions:In our data, estrogen therapy, particularly recent and long-term use, was associated with a substantial decrease in risk of fatal colon cancer. These results were consistent with several published studies suggesting a protective role of exogenous estrogens in the development of colorectal cancer and merit further investigation. (J Natl Cancer Inst 87: 517–523, 1995)