The risk of colorectal cancer is reduced among users of oral contraceptives or menopausal hormone therapy, but associations with reproductive characteristics that are markers of a woman's endogenous hormone milieu have not been consistently observed. To help understand possible mechanisms through which exogenous and endogenous hormonal exposures are involved in colorectal cancer, we assessed the risk of these malignancies according to tumor expression of estrogen receptor-β (ESR2). In a population-based study of postmenopausal women (503 cases and 721 controls matched for sex and age), immunohistochemical expression of ESR2 was determined in 445 cases of incident colorectal cancer. Unconditional logistic regression was used in case-case analyses to assess heterogeneity between risk associations according to ESR2 status and in case-control analyses to estimate associations separately for ESR2-negative and ESR2-positive tumors. For ESR2-positive tumors but not ESR2-negative tumors, colorectal cancer risk significantly decreased with duration of oral contraceptive use [per five-year increments OR ESR2-positive, 0.87, 95% confidence interval (CI), 0.77-0.99; OR ESR2-negative, 1.02, 95% CI, 0.91-1.15; Pheterogeneity = 0.07] and with duration of menopausal hormone therapy use (per five-year increments OR ESR2-positive, 0.84, 95% CI, 0.74-0.95; OR ESR2-negative, 0.94, 95% CI 0.84-1.05; Pheterogeneity = 0.06). Significant heterogeneity according to ESR2 expression was found for the association with current use of menopausal hormone therapy (<0.5 years ago; Pheterogeneity = 0.023) but not for associations with reproductive factors. In conclusion, our results suggest that hormone use decreases risk for ESR2-positive but not ESR2-negative colorectal cancer.