Background: Risk of ovarian malignancy algorithm (ROMA) combining human epididymis secretary protein 4 (HE4) and CA125 is a novel score, specific for epithelial ovarian cancer (EOC). Methods: Our cohort prospective study aimed to evaluate the role of HE4 and ROMA score in the diagnosis of EOC. We determined CA125 and HE4 serum levels in 56 premenopausal women with ovarian mass (38 women with benign ovarian mass and 18 women with malignant ovarian mass), 56 postmenopausal women with ovarian mass (20 women with benign ovarian mass and 36 women with malignant ovarian mass), and 56 healthy women as control. Results: Serum CA125 and HE4 and ROMA score were significantly higher among postmenopausal group compared with premenopausal and control groups (P< 0.001), and the median serum CA125 and HE4 and ROMA levels were statistically higher among malignant lesions compared with benign lesions and control group (P< 0.001). The sensitivity and specificity of HE4 and ROMA vs. CA125 in discriminating ovarian cancer from benign ovarian tumor was (88% and 98% vs. 90%) and (97% and 99% vs. 80%), respectively. ROMA had better sensitivity and specificity compared to CA125 and HE4 in premenopausal and postmenopausal women (P <0.001) In premenopausal patients, there was a statistically significant difference regarding the area under the curve (AUC) of ROMA vs. CA125 (P=0.004) and ROMA vs. HE4 (P =0.02). Conclusion: ROMA score showed a better performance in comparison with either CA125 or HE4 alone in premenopausal patients. HE4 and ROMA score significantly differentiated early from late stage ovarian cancer.