Background: Annexin A2 (ANXA2) and S100A4 proteins might have important roles as biomarkers in progression and metastasis of several tumors. Aim: The aim of this study was to investigate the expression of both ANXA2 and S100A4 in endometrioid carcinoma (EC) and to correlate their expression with the clinicopathological and prognostic features including patients' survival. Methods: ANXA2 and S100A4 immunohistochemical expression was analyzed in 54 samples of EC and 20 proliferative endometrium. The overall survival (OS) and disease free survival (DFS) were determined by Kaplan–Meier analysis. Results: ANXA2 and S100A4 overexpression was detected in 64.8% and 74.1% of EC respectively and that was significantly higher as compared with proliferative endometrium (P<0.001). ANXA2 expression was significantly correlated with tumor grade (P=0.011). Furthermore, a significant correlation was identified between ANXA2 and S100A4 expression and advanced FIGO stage (P=0.004, P=0.001 respectively), myometrial invasion (P=0.03, P=0.019 respectively), and lymph node metastasis (P=0.001, P<0.001 respectively). The expression of ANXA2 and S100A4 was positively correlated (Spearman correlation coefficient (r) = 0.501, P< 0.05). Kaplan–Meier survival curves revealed a significant relation between ANXA2 and S100A4 overexpression and reduced DFS (P=0.001, P= 0.015 respectively) and worse OS (P=0.008, P=0.034 respectively). Analysis of the co-expression of both markers revealed that ANXA2/S100A4 high expression group exhibited the lowest 3-years DFS and OS in EC patients as compared with the other groups. Conclusion: Combined detection of ANXA2 and S100A4 may serve as an important index to estimate the biological behavior and predict tumor progression and prognosis of EC.