Objectives: To evaluate the diagnostic accuracy of serum can- cer antigen 125 (CA125) and human epididymis protein 4 (HE4) in the prediction of malignant ovarian masses then to analyze the effect of personal criteria and medical diseases on this accuracy. Study Design: This prospective study was performed in Zagazig University Hospital. The eligibility criteria for inclu- sion were; consecutive women, at any age ≥18 years, with established diagnosis of ovarian mass based on symptoms, signs, and imaging techniques. All patients underwent per- sonal and medical history taking, preoperative serum CA125 and HE4 (cutoff35 IU/mL and 150 pmol/L, respectively) as- sessment then postoperative histopathologic examination of lesions as a reference standard. Results: Among the included 140 patients, 62 were con- firmed to have ovarian malignancy and 78 had benign le- sions. Serum CA125 ≥35 IU/mL was associated with ovarian malignancy at sensitivity 91.9%, specificity 53.8%, and accu- racy 70.7%. Raising its cutoffto 67.5 IU/mL decreased the sen- sitivity 83.9%, increased the specificity 80.7% with accuracy82.1%. The combination of HE4 and CA125 showed sensitiv- ity 75.8%, specificity 93.5%, and accuracy 85.7%. Women suf- fering from both diabetes mellitus and hypertension showed a significant decrease in CA125 concentration P = 0.02 with false negative results in (5/11) of them, making its sensitivity 54.5% in this condition. Conclusions: The performance of CA125 in cancer ovary pre- diction can be improved by increasing its cutoffor by com- bining CA125 with HE4. Diabetes mellitus and hypertension can influence CA125 performance while HE4 is independent on these factors. This can be an additional value of the intro- duction of HE4 in cancer ovary prediction protocols.