Clinically, elevated cancer antigen 125 (CA-125) in blood predicts tumor burden in a woman’s body, especiallyin the ovary, but cannot differentiate between malignant or benign. We here used intensive modern proteomicapproaches to identify predictive proteins in the serum of women with elevated CA-125 to differentiate malignantfrom benign ovarian tumors. We identified differentially expressed proteins in serum samples of ovarian cancer(OC) patients, benign ovarian tumor (BT) patients, and healthy control women using mass spectrometry-basedquantitative proteomics. Both the OC and BT patients had elevated CA-125. Quantitation was achieved usingisobaric tags for relative and absolute quantitation. We obtained 124 quantified differential serum proteins in OCcompared with BT. Two proteins, apolipoprotein A-4 (APOA4) and natural resistance-associated macrophage1, were verified using Western blotting. Proteome profiling applied to OC cases identified several differentialserum proteins in the serum of women with elevated CA-125. A novel protein, APOA4, has the potential to bea marker for malignant tumor differentiation in the serum of women with elevated CA-125.