We evaluated colorectal cancer risk associated with the duration and recency of specific menopausal hormone therapy formulations (i.e., unopposed estrogen versus estrogen plus progestin) and regimens (i.e., sequential versus continuous estrogen plus progestin use) among 56,733 postmenopausal women participating in the Breast Cancer Detection Demonstration Project follow-up study. Hormone therapy use and other risk factors were ascertained through telephone interviews and mailed questionnaires from 1979 to 1998. The final cancer group included 960 women who were identified from self-report, medical records, state registry data, and the National Death Index. Poisson regression was used to generate multivariable rate ratios (RR) and 95% confidence intervals (95% CI). We observed a decreased riskof colorectal cancer among ever users of unopposed estrogen therapy (RR, 0.83; 95% CI, 0.70-0.99). Among estrogen users, the largest reduced risk was observed for current users (RR, 0.75; 95% CI, 0.54-1.05) and users of zten years duration (RR, 0.74; 95% CI, 0.56-0.96). We found a reduced risk among users of estrogen plus progestin therapy (RR, 0.78; 95% CI, 0.60-1.02), with sequential regimen users (progestin <15 days per cycle) having the largest riskreduction (RR, 0.64; 95% CI, 0.43-0.95). Past users of ≥5 years ago (RR, 0.55; 95% CI, 0.32-0.98) had the largest risk reduction. In this study, estrogen plus progestin use, especially sequential regimen use, was associated with the largest overall reduction of colorectal cancer risk.