Background: Endometrial cancer (EC) incidence is rising, necessitating precise risk stratification for optimal therapy. ESMO-ESGO-ESTRO guidelines aid in determining lymph node dissection and adjuvant treatment. New prognostic markers are needed for accurate patient stratification. Our study aims to utilize preoperative IHC analysis of L1CAM, ER, PR, and p53 to enhance surgical planning and outcomes in EC patients. Patients and Methods: A retrospective-prospective cohort-study was conducted at multiple departments in Zagazig University Hospitals. Sixty patients with confirmed endometrial carcinoma scheduled for surgery between January 2019 and March 2022 were included. IHC staining for ER, PR, L1CAM, and p53 was performed and correlated with ESMO-ESGO-ESTRO guidelines and lymph node status. Results: Statistically significant correlations were found between IHC markers and histopathological findings, with abnormal-P53 and L1CAM not correlating with histological type and grade. Positive-ER/PR expression had a 3-year OS of 93.5%, while ER-negative patients had 64.3% (p = 0.002). Abnormal-P53 was linked to poorer OS (54.5%) compared to normal (93.9%) (p<0.001). L1CAM-negative patients had a better OS (94.2%) vs. L1CAM-positive (37.5%) (p<0.001). ER/ PR-negative, abnormal-P53, and L1CAM-positive patients had poorer PFS (35.7%, 18.2%, 12.5%) (p<0.001). Poorer RFS was seen in P53-abnormal, L1CAM-positive, ER/PR-negative, and high-risk ESMO-ESGO-ESTRO subgroups (p<0.001). High-risk ESMO-ESGO-ESTRO subgroups were independently associated with reduced PFS, as were L1CAM-positive and P53-abnormal patients (p=0.002, p=0.07). Conclusion: We concluded that pre-operative IHC-biomarkers (L1CAM and P53) could be used as refinement for lymph node directed surgery and also adjuvant selective treatment by being integrated in the ESMO-ESGO-ESTRO risk classification.