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Lower incidence rates of distal large bowel cancer in women when compared with men support the protective role of female hormones. We aimed to determine the associations between hormone replacement therapy, oral contraceptive use, and distal large bowel cancer.We conducted a population-based case–control study of incident distal large bowel cancer in North Carolina between 2001 and 2006. Data on hormone replacement therapy, oral contraceptive use, demographics, and risk factors were obtained through in-person interviews. Odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between oral contraceptive use, hormone replacement therapy, and distal large bowel cancer were estimated through unconditional logistic regression models overall, by duration of use, and within strata of race.There were a total of 443 women with distal large bowel cancer and 405 controls. Ever use of hormone replacement therapy was strongly associated with a reduced risk of distal large bowel cancer (OR 0.52, 95% CI 0.38–0.72). Further reduction of distal large bowel cancer risk occurred with increased duration of use (<4 years (OR 0.77, 95% CI 0.44–1.35), 4–8 years (OR 0.64, 95% CI 0.37–1.10), 9–14 years (OR 0.47, 95% CI 0.27–0.81), and ≥15 years (OR 0.34, 95% CI 0.20–0.58)). Ever use of oral contraceptives was not associated with reduced incidence of distal large bowel cancer (OR 0.95, 95% CI 0.67–1.34) nor was duration of use. There were no differences by race.Hormone replacement therapy is associated with a lower risk of distal large bowel cancer. This risk is further reduced with increased duration of use. Hormone replacement therapy may be partially responsible for the reduced incidence of distal large bowel cancer in women compared with men.