Objective: To evaluate the role of hormone replacement therapy (HRT) as a risk factor for the development of epithelial ovarian cancer. Methods: A case-control study was performed that used 491 patients with epithelial ovarian cancer frequency matched for age at diagnosis (±5 years) with a control population of 741 patients with malignancies of nonestrogen-dependent tissues. The odds ratio (OR) for the development of epithelial ovarian cancer was estimated using logistic regression analysis with adjustment for age at diagnosis, parity, oral contraceptive use, smoking history, family history of epithelial ovarian cancer, age at menarche, menopausal status, income, and education. Results: One hundred of 491 patients (20.4%) in the study population had ever used HRT, and 160 of 741 patients (21.6%) in the control population had ever used HRT (OR 0.85; 95% confidence interval [CI] 0.62, 1.2). A significant association between HRT and specific histologic subtypes of epithelial ovarian cancer was not demonstrable for serous cystadenocarcinoma (OR 1.2, 95% CI 0.8, 1.7), clear cell carcinoma (OR 1.1, 95% CI 0.4, 3.4), or endometrioid carcinoma (OR 0.4; 95% CI 0.2, 1.2). A significant association between duration of use of HRT and the risk of developing epithelial ovarian cancer was not demonstrable for under 5 years (OR 0.8; 95% CI 0.5,1.2), 5-9 years (OR 0.6; 95% CI 0.3, 1.1), or 10 or more years (OR 0.6; 95% CI 0.3, 1.4). Conclusion: A significant association between the use of HRT and the risk of developing epithelial ovarian cancer, even with prolonged exposure, is not demonstrable.