Objective: Ovarian cancer has the highest mortality of all the gynecologic malignancies with most patients diagnosed at late stages. Serum CA-125 is elevated in only half of patients with stages I-II. We identified 3 serum proteins (apolipoprotein A-1, transthyretin, and transferrin) for the detection of ovarian cancer and reported them combined with CA-125 to effectively detect early-stage mucinous tumors. The objectives of this study were to assess the effectiveness of the panel in detection of early-stage serous and endometrioid ovarian cancers. Study Design: In all, 358 serum samples (control, benign adnexal masses, and early-stage and late-stage ovarian cancer) were obtained from the National Cancer Institute. The level of each marker was measured. Multiple logistic regression models were built to calculate sensitivity and specificity. Results: When combined with CA-125, the panel detected early-stage cancer with a sensitivity of 96%. The highest sensitivity was seen for detection of endometrioid subtype of early-stage carcinomas (98%). Conclusion: A panel of 4 serum biomarkers effectively detected early-stage ovarian cancers with the highest reported overall sensitivity of 96%. Endometrioid tumors were detected at early stages with a sensitivity of 98%. Prospective clinical analysis of the panel is needed to validate it as an effective screening tool for early-stage ovarian cancer. © 2009 Mosby, Inc.