OBJECTIVE--To assess whether tubal ligation and hysterectomy affect subsequent risk of ovarian cancer. DESIGN--Prospective cohort study with 12 years of follow-up. SETTING--United States, multistate. PARTICIPANTS--A total of 121,700 female registered nurses who were 30 to 55 years of age in 1976; the follow-up rate was 90% as of 1988. MAIN OUTCOME MEASURE--Ovarian cancer of epithelial origin confirmed by medical record review. RESULTS--We observed a strong inverse association between tubal ligation and ovarian cancer, which persisted after adjustment for age, oral contraceptive use, parity, and other ovarian cancer risk factors (multivariate relative risk [RR], 0.33; 95% confidence interval [CI], 0.16 to 0.64). The association was similar when we assessed tubal ligation status at the baseline questionnaire and excluded cases in the first 4 years to eliminate any possible short-term decrease in risk due to screening of the ovaries during ligation surgery. We noted a weaker inverse association between simple hysterectomy and ovarian cancer (RR, 0.67; 95% CI, 0.45 to 1.00). Neither vasectomy nor condom use by a partner was associated with risk of ovarian cancer. CONCLUSIONS--These data indicate that tubal ligation, and perhaps hysterectomy, may substantially reduce risk of epithelial ovarian cancer.