Objective: To evaluate the diagnostic performance of cancer antigen CA-125, CA72-4, human epididymis protein 4 (HE-4), and macrophage colony stimulating factor (M-CSF), separately or in combination in the diagnosis of early-stage ovarian cancer. Materials and Methods: This was a prospective case control study conducted in a University Gynecology hospital. A total of 127 patients with ovarian cancer, in Stage I (n=40) and Stage II (n=87), and 128 age-matched healthy women (controls) were included. CA-125, CA72- 4, HE-4, and M-CSF serum levels were assessed and compared in patients vs. controls. Results: Seventy-six patients were menopausal (59.8%). A significant difference between cases and controls were detected in terms of each of the serum level of the studied markers.The diagnostic performance for the studied markers in patients in Stage I, namely ; CA 125, CA 72-4, HE-4, and M.CSF, showed sensitivities of 50%, 7%, 68.42%, and 32.14%, respectively. Applying the logistic regression model for all studied markers significantly increased the sensitivity and confirmed a better diagnostic performance in Stage I, when combining the four markers together, with area under the curve (AUC) of 0.978, and a sensitivity of 91.07, at a fixed specificity of 90%. Conclusions: Using non-invasive and simple markers' panel for early detection of ovarian cancer is the ultimate goal for the best clinical practice. Based on the present results, the authors suggest using the four studied markers in combination for satisfactory and reliable diagnostic performance.