Background: The basis of cancer management is understanding its underlying molecular abnormalities. To improve the survival of ovarian cancer patients, new therapeutic targets and prognostic markers are needed. SMYD3 and CDK9 are two markers that play an important role in epigenetic regulation and promotion of the oncogenic process. They have to be under investigation to be used as targets for therapy. This study aims at evaluating the diagnostic and prognostic value of the immunohistochemical expression of SMYD3 and CDK9 in serous ovarian carcinoma (SOC). Methods: 50 cases of SOC and 50 benign ovarian lesions cases were included in this study. The morphological classification was assessed according to the World Health Organization criteria. Immunohistochemistry (IHC) for CDK9 and SMYD3 was performed. Results: SMYD3 and CDK9 was highly expressed in cancer compared with benign lesions (p <0.001 and <0.05 respectively). High CDK9 and SMYD3 expression were significantly associated with vascular invasion and advanced stage disease (p <0.001 for both). Patients who exhibited high SMYD3 and CKD9 expression showed poor treatment response, drug resistance and higher frequency of relapse and mortality. Conclusion: The immunohistochemical staining of SMYD3 and CDK9 is higher in serous ovarian carcinoma compared with benign ovarian lesions and represents a worse prognostic factor