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Background: The deregulation and localization of the Annexins is consistently reported to have close relation to tumor cell malignancy, invasion, and metastasis as well as clinical progression of tumors. This study aimed to evaluate serum Annexin A2 (Anx A2) levels in patients with colon cancer in comparison to healthy controls and in relation to demographics and tumor pathology., Material and Methods: A total of 100 patients (mean (SD) age: 58 (5.8) years, 55.0% females) with colon cancer and 70 controls (mean (SD) age: 59 (5.4) years, 50.0% females) were included. Serum levels for Anx A2 were evaluated in relation to study group, demographics, and tumor pathology., Results: Serum levels for Anx A2 were significantly lower in patients with colon cancer than in controls (13.1 (4.5) vs. 22.8 (2.1) ng/mL, p<0.001) and significantly decreased with increase in tumor size (p=0.003), and at higher stages of TNM (p=0.004), tumor invasion (p=0.005), lymph node metastasis (p=0.003), and distant metastasis (p=0.005)., Conclusions: Our findings indicate a significant decrease in Anx A2 expression in colon cancer patients compared to healthy controls and in parallel with tumor progression.