Abstract Menopausal hormone therapy has been associated with a reduced risk of colorectal cancer yet few studies have evaluated cancer risk by specific formulations (i.e., estrogen versus estrogen plus progestin) or regimens (i.e., sequential versus continuous estrogen plus progestin). We prospectively analyzed colorectal cancer risk associated with duration and recency of specific menopausal hormone therapy formulations and regimens among 121,891 postmenopausal women participants of the National Institutes of Health-AARP Diet and Health Study. Hormone therapy use and other risk factors were ascertained through two questionnaires in 1995–1996 and 1996-1997. We used state cancer registry and vital status databases to identify 1,141 women who were newly diagnosed with invasive colorectal cancer during 653,774 years of follow-up. We used multivariable Cox proportional hazards regression to estimate relative risks (RRs) and 95% confidence intervals (95% CIs) of colorectal cancer relative to never-use of menopausal hormone therapy. Use of only unopposed estrogen was associated with a statistically significant 30% reduced risk of colorectal cancer (RR, 0.70; 95% CI, 0.56–0.87). The greatest risk reduction in estrogenonly users occurred among current, medium duration (6–9 years) users (RR, 0.49; 95% CI, 0.28-0.85). Women who used exclusively estrogen plus progestin had a marginally-significant 17% reduced risk of colorectal cancer (RR, 0.83; 95% CI, 0.68–1.00). The greatest risk reduction in this therapy formulation group occurred among current users of short duration (<5 years) (RR, 0.73; 95% CI, 0.52–1.04). With respect to regimen, both continuous (progestin ≥ 15 days per cycle: RR, 0.82; 95% CI, 0.65–1.03) and sequential (progestin < 15 days per cycle: RR, 0.84; 95% CI, 0.62–1.13) users of estrogen plus progestin had similarly reduced risks, neither of which was statistically significant. Among those on a continuous regimen, current use of short duration (<5 years) was associated with a statistically significant 45% reduced risk of colorectal cancer (RR, 0.65; 95% CI, 0.43–0.98). Our data indicate that both unopposed estrogen and estrogen plus progestin menopausal hormone therapies are associated with a reduced risk of colorectal cancer and that the degree of risk reduction varies by duration and recency of use. Citation Information: Cancer Prev Res 2010;3(1 Suppl):B133.