Background and Purpose: Ovarian cancer is the leading cause of death among gynecologic cancers because of the lack of effective early detection methods. Accuracies of the human epididymis protein 4 (HE4) and mesothelin in detecting ovarian cancer have never been systematically assessed. The current systematic review aimed to tackle this issue. Methods: MEDLINE, EMBASE, and Cochrane databases were searched (September 1995-November 2011) for studies on the diagnostic performances of HE4 and mesothelin in differentiating ovarian cancer from other benign gynecologic diseases. QUADAS items were used to evaluate the qualities of the studies. Meta-DiSc software was used to handle data from the included studies and to examine heterogeneity. All included studies for diagnostic performance were combined with sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratios (DORs) with 95% confidence intervals (CIs), summary receiver operating characteristic (SROC) curves, and areas under the SROC curves (AUC). Results: A total of 18 studies and 3,865 patients were eligible for the final analysis. The pooled sensitivity estimates for HE4 (74.4%) were significantly higher than those for mesothelin (49.3%). The pooled specificity estimates for mesothelin (94.5%) were higher than those for HE4 (85.8%). The pooled DOR estimates for HE4 (26.22) were higher than those for mesothelin (24.01). The SROC curve for HE4 showed better diagnostic accuracy than that for mesothelin. The PLR and NLR of HE4 were 6.33 (95% CI: 3.58 to 11.18) and 0.27 (95% CI: 0.21 to 0.34), respectively. The PLR and NLR for mesothelin were 11.0 (95% CI: 6.21 to 19.59) and 0.51 (95% CI: 0.42 to 0.62), respectively. The combination of the two tumor markers or their combination with CA-125 increased sensitivity and specificity to different extents. Conclusion: The diagnostic accuracy of HE4 in differentiating ovarian cancer from other benign gynecologic diseases is better than that of soluble mesothelin-related protein. Combinations of two or more tumor markers show more sensitivity and specificity.