Human Epididymis Protein (HE4) is a new promising biomarker in detecting recurrent ovarian cancer. In this study, we investigated the role of serum HE4 in comparison to CA125 in the detection of recurrent disease in patients during follow-up.615 ovarian cancer patients treated at Shandong Provincial Tumor Hospital between 2008 and 2014 were included in the retrospective study. Serum HE4 and CA125 were analyzed during follow-up using the ARCHITECT assay. 131 patients developed recurrent disease. Results showed that a serum HE4 level of 70pmol/L was associated with a sensitivity of 76.3%, a specificity of 89.6%, a negative predictive value of 93.3% and a positive predictive value of 66.6% when assessing for recurrent ovarian cancer whereas CA125 was associated with a sensitivity of 54.9%, a specificity of 79.3%, negative predictive value of 86.6% and a positive predictive value of 41.8%. However, combining CA125 and HE4 at a cut-off of 70pmol/L, the sensitivity, specificity, negative predictive value and positive predictive value increased to 83.9%, 90.9%, 95.4% and 71.4% respectively. These data suggest HE4 is a more sensitive and specific predictor of recurrent disease and should therefore be incorporated with CA125 in detection of recurrent ovarian cancer.