The benefits and risks of estrogen replacement therapy continue to confuse women and their physicians. Recent evidence suggests that estrogen replacement may be associated with reductions in large bowel cancer, a common disease among postmenopausal women. Further study of this potentially important association would provide more precise estimates of the magnitude of effect, identify salient patterns of use, and, importantly, supply insights into the biology of this tumor in women. A population-base case-control study is proposed to evaluate the association between postmenopausal hormones and the occurrence of colorectal cancer. This study will specifically assess use of estrogens with and without progestin, the duration and currency of hormone use, and inter-relationships with body mass. Additional aims of this study are to elucidate the mechanisms of this inverse association, specifically the relationship of HRT to hormone receptors and proliferation in the bowel, and to examine the modifying role of more common cancer susceptibility genes influencing the metabolism of estrogens. Over a three year period, interviews will be conducted with 1,100 women with newly diagnosed cancer of the colon or rectum selected from the population. In addition to the structured telephone interview, fixed diagnostic tissue will be obtained from 540 case in order to evaluate estrogen-receptor status and proliferation markers. Blood samples on a sample of 600 (most with diagnostic tissue) cases and 600 controls will be obtained for genetic studies of polymorphisms relevant to estrogen metabolism and function, specifically CYP17 and the estrogen receptor gene. The proposed study and its extensions should provide clear evidence for the degree to which HRT is protective against colorectal cancer and permit the determination of some of the relevant pathways for that protection.