Objective: To evaluate the performance of mesothelin, CA125, HE4 and ROMA index in the detection of malignant ovarian tumors. Study Design: This is a cross-sectional study including 199 women with adnexal masses (67 with malignant tumors and 132 with benign tumors) and 150 healthy women (controls). We used a recursive multivariate partitioning algorithm to assess the contribution of each of the serum markers and the ROMA index to the discrimination of women with malignant tumors. Also, the areas under the ROC curves (AUC) for each of the serum markers and for the ROMA index were compared using the Venkatraman's projection-permutation test. Results: In the recursive model, CA125 had the best performance in discriminating women with malignant tumors. In women with normal-range CA125 levels, none of the other markers contributed to the discrimination of women with malignant tumors. In women with elevated CA125 levels, elevated HE4 levels were associated with an increased risk of harboring a malignant tumor. The AUC for mesothelin was smaller than that for all the other curves, and both the ROMA index and CA125 had better AUC than HE4. Conclusion: In women with normal CA125 levels, neither mesothelin nor HE4 contributed to discriminate women with malignant ovarian tumors; however, for women with elevated CA125 levels HE4 may help discriminating those who have a malignant ovarian tumor.