To explore the roles of reproductive factors and oral contraceptive use in the etiology of colorectal cancer, we examined incident cases of colorectal cancer (n = 501) that occurred during 1,012,280 person-years of follow-up between 1980 and 1992 in the Nurses' Health Study. The women completed mailed, self-administered questionnaires every 2 years to update information on the risk factors and major medical events. In multivariate analysis, the relative risk (RR) of colorectal cancer among women who experienced menarche at age 14 or older was 0.83 (95% confidence interval (CI) = 0.64-1.08) compared with women who had menarche at age 13; women whose menarche occurred under age 12 were at higher risk (RR = 1.22; 95% CI = 0.96-1.55, P for trend = 0.01). Compared with women whose first pregnancy was before age 24, the risk for colorectal cancer was significantly increased among women whose first pregnancy was at age 30 or older (RR = 1.57; 95% CI = 1.15-2.14; P for trend = 0.02). No important associations were seen for parity or age at menopause. Women who used oral contraceptives for 96 months or longer had a 40% lower risk of developing colorectal cancer (RR = 0.60; 95% CI = 0.40-0.89; P for trend = 0.02) compared with women who never used oral contraceptives. These prospective data suggest that a later age of menarche and use of oral contraceptives may reduce risk of colorectal cancer, whereas women with a later age at first pregnancy may have a higher risk.