Background Colorectal cancer (CRC) is a foremost global health concern and remains one of the major causes of cancer-related morbidity and mortality. It is the third most common cancer in adults after lung cancer and breast cancer worldwide. The theory that cancer originates from a subpopulation of tumor cells, named cancer stem cells (CSC), they have important role of CSC in the initiation and maintenance of the tumor, as well as invasion, metastasis and therapeutic resistance. Among CSC markers, CD44 and OPN are two of the most investigated colorectal CSC markers and their proteins are introduced as the subpopulation with a greater tumorigenicity. This study aiming assessing the immunohistochemical expression of CD44 & OPN in colorectal adenomas & CRCs. And their relation between immunohistochemical expression of CD44 & OPN with tumor differentiation (grading), lympho-vascular invasion, perineural invasion, desmoplasia and TNM stage. Methods this is a retrospective descriptive study that included Sixty paraffin embedded blocks from the pathology laboratory, Suez Canal University Hospital. Paraffin blocks included (14 cases of colorectal carcinoma and 18 cases of colorectal adenoma). paraffin blocks reviewed for clinicopathological prognostic factors and stained by CD44 & OPN, monoclonal antibodies by immunohistochemical method. Results The CD44 protein was overexpressed in 80% of CRC, while was positive (44.4%) in adenoma this difference was statistically significant. Also, in this study the difference between the expression OPN in CRC and adenomas was statistically insignificant. Conclusions CD 44 is highly expressed in large number of CRC (80 of tumors). It is also significantly more expressed in CRC than in adenomas, suggesting a role of CD 44 in CRC tumorigenesis and progression of adenomas into carcinomas. Our study also associated CD 44 overexpression with both late TNM stage and lympho-vascular invasion.