Background: Cyclooxygenase (COX) is a rate limiting enzyme in synthesis of prostanoids pathway and it has 2 isoforms (COX-1 and COX-2). It has many biological roles in inflammation and oncogenesis. Cox-2 was incriminated in performing disturbances in the cell cycle control in CRC, but its role of in CRC needs clarification of the mechanisms by which Cox-2 might affect the process of colorectal carcinogenesis. Cyclin D1 is an oncogene that regulates G1 phase progression to S phase of the cell cycle. Its stimulatory role on cell cycle is antagonized by Cyclin D1-dependent kinase (CDK) inhibitors like p21. P21 plays an essential role in cell cycle regulation; it may have a pro-apoptotic or an antiapoptotic role in cancer. P21 was found to have many roles in cancer; invasion metastases, cellular senescence and stem cells aging. The roles of combined expression of Cox-2, Cyclin D1 and P21 in CRC tissues and their role of prognosis and patients survival are not sufficiently clarified. Aim of the Study: To evaluate tissue expression of Cox-2, Cyclin D1 and P21 in CRC and to correlate such expression with pathological parameters, clinical and prognostic data of the patients. Methods: Cox-2, Cyclin D1 and P21 are evaluated in colon cancer tissues. Correlations between their level of expressions pathological parameters, clinical and prognostic data of patients were analyzed. Results: Cox-2, Cyclin D1 over-expression was associated with higher grade, higher incidence of occurrence of lymph node & distant metastasis and advanced stage (P = 0.000). Cox-2 was related to higher tumor recurrence rate (P = 0.04) and decreased overall patients survival rate (p = 0.002). (r correlation coefficient = +0.987). Conclusion: Cox-2 and Cyclin D1 are markers of poor prognosis colon cancer patients.