Background: P16 is known as a tumor suppressor protein. This study was conducted to evaluate the association of P16 expression and pathogenesis of colorectal cancer. The presence of P16 in cancerous and non-cancerous colorectal tissue samples were thus compared using immunohistochemistry method. Methods: In this stud, 50 paired tissue samples were provided. The pairs were comprised of samples of cancerous colorectal tissue and normal peers from non-cancerous tissue adjacent to cancerous ones. Expression of P16 was studied on paraffined sections using immunohistochemistry method. Findings: Although P16 was expressed in all tissue samples, we found a lower expression in colorectal cancerous tissue in comparison with normal tissue samples. This difference was revealed to be statistically significant (P < 0.001). Conclusion: The presence of P16 can be regarded as an appropriate biological marker and a valuable prognostic factor for colorectal cancer. Keywords: Colorectal cancer, Immunohistochemistry, Tumor suppressor gene, P16INK4a