Epithelial ovarian cancer (EOC) is treated mainly by platinum-based combination chemotherapy. Chemotherapy induces apoptosis in which the Fas/Fas ligand pathway is important. Serum soluble Fas (sFas) is a biomarker of this pathway and functionally inhibits Fas-/FasL-mediated apoptosis. In this study, we have investigated the role of sFas in prediction of response to chemotherapy in EOC. Thirty-five patients were recruited and their serum sFas levels were estimated by ELISA at 4 time points—preoperative (sFas1), postoperative (sFas2), midchemotherapy (sFas3) and at the end of chemotherapy (sFas4). The response to chemotherapy was documented clinically, radiologically and by CA-125 levels, based on which, 2 groups were identified: primary chemosensitive (n = 24) and primary chemoresistant (n = 11). Based on the disease status at last follow-up, 2 groups were identified: No Evidence of Disease (n = 15) and Evidence of Disease (n = 20). The primary chemoresistant tumors showed significantly higher median sFas2 levels (p = 0.033) with the sFas2/sFas1 ratio ≥1 (p = 0.001). A multivariate Cox proportional hazards regression model identified sFas2/sFas1 ratio as a significant factor for the prediction of response to platinum-based chemotherapy (p = 0.011). Receiver operating characteristic (ROC) analysis showed that at a ratio of 1.2, sFas2/sFas1 achieved a sensitivity of 82% and specificity of 100% for prediction of chemotherapeutic response. sFas2/sFas1 and sFas3/sFas1 ratio was also higher in patients with evidence of disease (p = 0.018 and p = 0.028, respectively). Progression-free survival rates in patients with sFas2/sFas1 ratio <1 exceeded those with ratio ≥1 (p = 0.004). In conclusion, serum sFas is a useful biomarker for predicting response to platinum-based chemotherapy in EOC. © 2007 Wiley-Liss, Inc.