Abstract: Objective To investigate the expressions of serum human epididymis protein 4 (HE4) and carbohydrate antigen 125(CA125) in epithelial ovarian cancer (EOC), and analyze their relationships with prognosis. Methods One hundred and thirty-eight patients with EOC (EOC group), 106 patients with benign epithelial ovarian tumors (benign group) and 106 healthy women (control group) selected from January 2011 to December 2014 in the Central Hospital of Western Hainan were included in this study. The serum levels of HE4 and CA125 were detected by chemiluminescence method. Kaplan-Meier curve and COX regression analysis were performed to explore prognostic factors of EOC. Results The levels of serum HE4 and CA125 in EOC group were significantly higher than those in benign group and control group HE4 (pmol/L): (309.42±56.83) vs (57.26±15.48) and (51.30±11.36); CA125 (U/ml): (80.37±30.65) vs (26.43±11.48) and (21.75±9.62), all P< 0.01. Cox regression analysis showed that clinical stage HR(95% CI): 1.842 (1.395-2.641), lymph node metastasis HR(95% CI): 3.714 (2.875-5.129), tumor recurrence HR(95% CI):4.315 (3.162-6.248), HE4 HR(95% CI): 1.936 (1.416-2.758) and CA125 HR(95% CI): 1.527 (1.124-2.260) expression were independent prognostic factors for EOC (All P< 0.01). Conclusion HE4 and CA125 levels increase significantly in EOC, which are the risk factors for poor prognosis.