The aim of this study was to evaluate serum human epididymis protein 4 (HE4) concentrations for the diagnosis and preoperative prediction of optimal debulking in epithelial ovarian cancer. The concentrations of serum HE4 and CA125 in 180 epithelial ovarian cancer patients, 40 benign ovarian tumor patients and 40 healthy female subjects were determined using enzyme-linked immunosorbent assays (ELISAs). The value of determining the serum HE4 concentrations for the diagnosis and preoperative prediction of optimal debulking in epithelial ovarian cancer was also analyzed. The concentration of serum HE4 was 355.2±221.29 pmol/l in ovarian cancer, 43.86±20.87 pmol/l in benign ovarian tumors and 30.22±9.64 pmol/l in healthy individuals, respectively. The serum HE4 levels of patients with ovarian cancer were significantly higher compared with those in the other two groups (P<0.01), although there were no statistically significant differences (P>0.05) between the benign ovarian tumors and healthy individuals. The maximum diagnostic value was identified at an HE4 serum concentration of 67.52 pmol/l and the sensitivity and specificity were 84 and 96%, respectively. The area under the ROC curve was 0.944 (95% CI, 0.912–0.976; P<0.001) and the κ value of the diagnosis of epithelial ovarian cancer according to HE4 was 0.814 (P=0.000). The demarcation criterion was 600 pmol/l, where a value >600 mol/l indicates a lower possibility of optimal debulking. HE4 predicted that the sensitivity of the incomplete cytoreductive surgery was 77% and specificity was 32%. The concentration of serum HE4 is a useful marker for diagnosis and preoperative prediction for the ideal tumor cytoreductive surgery in epithelial ovarian cancer.