Background There are conflicting data regarding the role of sex hormones in colorectal cancer development. Whereas clinical trials data indicate that hormone therapy use reduces the risk of colorectal cancer, data from prospective cohort studies suggest that circulating estrogen levels are positively associated with colorectal cancer risk. A surrogate measure of lifetime estrogen exposure is reproductive history. We investigated the relationship between reproductive factors and the risk of colorectal cancer. Methods Subjects were postmenopausal women enrolled in the National Institutes of Health-American Association of Retired Persons Diet and Health Study, a cohort of 214162 individuals (aged 50-71 years) that included 2014 incident cases of colorectal cancer that occurred over a mean follow-up of 8.2 years. Questionnaires were used to collect data on reproductive factors, including ages at menarche, birth of first child, and menopause; parity, and use of oral contraceptives. Multivariable Cox proportional hazards models were constructed to examine associations between these reproductive factors and the risk of colorectal cancer, with adjustment for established colorectal cancer risk factors. All statistical tests were two-sided. Results Age at menopause (≥55 vs <40 years: hazard ratio [HR] = 1.50, 95% confidence interval [CI] = 1.23 to 1.83; Ptrend =. 008) and age at birth of first child (≥30 vs ≤19 years: HR = 1.26, 95% CI = 1.01 to 1.58; Ptrend =. 05) were positively associated with the risk of colorectal cancer. Among women with no history of hormone therapy use, age at menarche (≥15 vs 11-12 years: HR = 0.73, 95% CI = 0.57 to 0.94; Ptrend =. 02) and parity (≥5 children vs no children: HR = 0.80, 95% CI = 0.63 to 1.02; Ptrend =. 10) were inversely associated with the risk of colorectal cancer. Conclusion These data support a role for sex hormones in colorectal tumorigenesis and suggest that greater endogenous estrogen exposure may increase the risk of colorectal cancer in postmenopausal women.