Background: Colorectal cancer (CRC), the third leading cause of cancer death worldwide, shows rising incidence in developing countries. A combination of environmental and genetic/epigenetic factors contribute to CRC development. Adenocarcinoma not otherwise specified (NOS) is the most common histopathologic subtype. Annexin A2 (ANXA2) is a calcium-regulated phospholipid-binding protein. Objective: Evaluation of the ANXA2 immunohistochemical (IHC) expression in colorectal adenocarcinoma compared to normal mucosaand adenoma and investigating its association with clinicopathological parameters in CRC and adenoma cases.  Materials and Methods: This retrospective study included 108 formalin-fixed, paraffin-embedded tissue blocks divided into three groups: adenocarcinoma, normal mucosa, and adenoma. Immunohistochemical staining by ANXA2 antibody was done, followed by semiquantitative evaluation of staining and correlation with clinicopathological data.  Results: High ANXA2 expression was significantly increased in CRC compared to normal mucosa and adenoma. Correlation of epithelial and stromal ANXA2 expression with clinicopathological parameters showed a significant association with aggressive cancer phenotypes including higher grade (P =0.003 and<0.001), large size (P = 0.006 and<0.001), deeper depth of invasion (P = 0.003 but 0.084 in stroma), advanced stage (P <0.001 for both), lymph node metastasis (P= 0.001 and <0.001), low lymphocytic infiltration (P <0.001 for both) and high tumor budding grade (P = 0.005 and <0.001). Conclusion: The association of Annexin A2 with aggressive tumor characteristics points to its potential involvement in tumor development, invasion, and metastasis.