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Uterine papillary serous carcinoma (UPSC) is a highly aggressive subtype of endometrial carcinoma. Histopathologically, it resembles the pattern of serous papillary carcinoma of the ovary. Cancer antigen 125 (CA-125) is the most widely used biomarker in epithelial ovarian carcinoma. Its use in UPSC evaluation has yet to be determined. The purpose of this study was to investigate the significance of preoperative serum CA-125 as a prognostic factor in patients with UPSC.The study cohort included all women with UPSC operated in our institution between January 2002 and June 2016. All patients underwent complete surgical staging. Preoperative CA-125 was reviewed and correlated with clinical and pathological parameters.Sixty-one women met the study criteria. Median preoperative CA-125 was found to be significantly associated with disease stage. Patients with disease stages I to IV had median preoperative CA-125 levels of 12.15, 19.6, 22.6, and 177.5 U/mL (P < 0.0001) respectively. Levels of CA-125 were significantly associated with positive cytology (P < 0.0001), omental disease (P < 0.0001), pelvic or para-aortic lymph node metastasis (P < 0.0001), and adnexal involvement (P < 0.0001). The optimal cutoff that provided the best sensitivity and specificity for omental and parametrial involvement as well as positive cytology was 57.5 U/mL. For adnexal and lymph node involvement, the optimal cutoff value was 41.8 U/mL.In patients with UPSC, preoperative CA-125 level correlates with known prognostic parameters of endometrial carcinoma and is associated with extrauterine involvement. These data should stimulate the need for further evaluation of the role of CA-125 in predicting recurrence and survival in UPSC.