Background Endometrial cancer (EC) is common type of gynecologic malignancy affecting a large number of females around the world. While most early stage cases are well managed with a relatively benign prognosis, the late stage cases have poor survival. Among the many biomarkers identified, serum human epididymis protein 4 (HE4) and CA125 are most promising surrogates for EC detection. Methods: We performed a meta-analysis to estimate the diagnostic accuracy of HE4 and CA125 and compared their performance. A literature research was performed in Medline, Cochrane Literature Library and CNKI. After filtering, twelve studies evaluating the diagnostic value of serum HE4, alone or in comparison with CA125, were included. The total sample size was 1106 patients and 1480 controls. Pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR) and diagnostic odds ratio (DOR) were calculated and summary receiver operating characteristic (SROC) curves were plotted to assess the diagnostic accuracy. Results: The pooled estimates for HE4 were sensitivity: 0.71 (95%Cl 0.56-0.82), specificity: 0.87 (95%Cl 0.80-0.92), and area under ROC curve: 0.88 (0.85-0.91), compared to 0.35 (95% CI 0.25-0.46), 0.83 (95% CI 0.71-0.91), and 0.58 (95% CI 0.54-0.63), respectively, of CA125. Subgroup analysis demonstrated a better performance of HE4 in Caucasian population, compared to Chinese population. Conclusion: This analysis suggested that when stage and histological type are not specifically considered, serum HE4 is generally a better tool than CA125 in EC diagnosis by its significantly higher sensitivity than CA125.