Background and aim: Endometrial cancer (EC) is a common gynecological cancer ranks as fifth cancer worldwide and the tenth common cancer in Egypt. There are two types of EC Type I and type II. Termed DEL 1(EGF like repeats and discoid domains 3), is an embryonic endothelial cell protein. EDIL3 has been associated with regulation of angiogenesis. SOX (sex-determining region Y-related high-mobility-group box transcription factor) gene family includes 20 members. SOX4 expression was altered in many human cancers. The aim of this study was to study expression of EDIL3, SOX4 in endometrial cancer in a trial to explore their relationship with clinicopathological parameters prognostic and treatment outcome. Patients and methods: Retrospective study included 50 paraffin blocks of cases of endometrial adenocarcinoma (endometroid type) with different grades, that was selected from the archives of the Pathology Department, Zagazig University, Egypt during a period from Jan 2015 to last of Dec 2019. The expression of EDIL3, SOX4 was evaluated using immunohistochemistry. Results: Fifty-six percent of the studied patients were >45 years old. Fifty-four percentage had well differentiated adenocarcinoma and 56% absent lymph node metastasis. EDIL3 and SOX4 expression is found in 70% and 84% of the studied. A statistically significant relation detected between EDIL 3 and tumor grade, stage, LVI (lympho-vascular invasion) and lymph node metastasis (p value was 0.001, <0.001,0.002 and 0.005 respectively). SOX4 was significantly correlated with tumor grade, stage, lymph node metastasis and LVI (p value was 0.039, 0.002, 0.006 and 0.015). Statistically significance relation was found between both EDIL3, SOX4 expressions and treatment response with p value 0.021 and = <0.001 respectively. Conclusion: EDIL3 and SOX4 expressions are associated with advanced clinicopathological parameters, unfavorable prognosis and poor treatment response in endometrial adenocarcinoma.