Objectives: To evaluate cyclooxygenase-2 (COX-2) over-expression in colorectal cancer (CRC) and its role in carcinogenesis and prognosis.Methods: It was a retrospective study. Archival samples were obtained from Pathology Department at King Fahad Hospital, Madinah, Saudi Arabia, over 11 years' period (January 2006 to December 2017). Samples were analyzed using immunohistochemistry for COX-2 and Ki67 over-expression in 324 CRC patients, 40 cases of colorectal adenomas and 20 cases of normal colonic mucosa.Results: Cyclooxygenase-2 over-expression was observed in 40% of normal colonic mucosa, 65% of colorectal adenoma and 84.6% of CRC cases. There were no significant correlations between COX-2 over-expression and age, gender, tumor site, or tumor size. However, COX-2 over-expression revealed highly significant correlations with tumor differentiation, lymph node metastasis, lympho-vascular invasion, distant metastasis, advanced stages, and high Ki67 expression. Univariate Kaplan-Meir survival analysis showed that patients with high COX-2 expression had significantly shorter periods of survival. Multivariate analysis by means of the COX-2 regression model revealed that high COX-2 over-expression, AJCC, and Ki67 expression were the only significant independent prognostic indicators.Conclusion: Cyclooxygenase-2 over-expression increases during normal-adenoma-carcinoma sequence, moreover COX-2 over-expression is associated with advanced tumor stage and Ki67 over-expression. These findings suggest a significant role of COX-2 in the carcinogenesis and prognosis of CRC in our study population.