Colon cancer is the fourth most common cancer in the world, while rectal cancer ranks the eighth among all cancers. Together (colorectal carcinomas; CRC) are the third most common cancer diagnoses all over the world and the second most deadly cancer in the world after lung cancer. In Egypt and according to WHO statistics, the colon cancer ranks the eighth most common cancer. It represents 2.7% of the total cancers and 2.4% of the total cases of death from cancer. Cancer stem cells (CSCs) play a critical role in the metastasis and relapse of colorectal cancer. Colorectal CSCs are defined with a group of cell surface markers, such as CD44, CD133, CD24, EpCAM, LGR5 and ALDH. They are highly tumorigenic, chemoresistant and radioresistant and thus are critical in the metastasis and recurrence of colorectal carcinoma and disease-free survival. The aim of current study is to investigate the relation between CD44 and ALDH1A1expression and the clinicopathological features of CRC. Methods: Immunohistochemical staining for ALDH1A1 and CD44 was performed on 70 randomly selected tissue blocks of primary colorectal adenocarcinoma and their lymph node, including fifty-three (75.7%) of cases were conventional adenocarcinomas (NOS), 7 (10%) cases were mucinous carcinoma and 10 (14.3%) cases were Signet ring carcinoma. Results: As regarding ALDH1A1, high expression was detected in 52 (74.3%) of cases. A statistically significant association was observed between ALDH1A1 high expression and higher tumor grade, poorly differentiated clusters (PDCs) grade, regional lymph node involvement, Lymphovascular invasion (LVI) advanced tumor stage, tumor necrosis and tumor infiltrating lymphocytes (P value> 0.001, <0.001, <0.001, <0.001, <0.001, P 0.038 and 0.002). As regarding CD44, high expression was detected in 43 (61.4%) of cases. A statistically significant association was observed between CD44 high expression and larger tumor size, higher tumor grade, poorly differentiated clusters (PDCs) grade, regional lymph node involvement, Lymphovascular invasion (LVI) advanced tumor stage, tumor necrosis and tumor infiltrating lymphocytes (P value 0.046, <0.001, <0.001, <0.001, <0.001, <0.001, <0.001 and 0.021). Association of ALDH1A1 and CD44 expression with different clinicopathological variables were further tested using univariate and multivariate regression analysis. The current study found that tumor grade, PDCs grade, modified Dukes staging, lymphovascular invasion and tumor necrosis were independently associated with ALDH1A1 expression (P value 0.034*, 0.022*, 0.047*,0.035*, 0.013 respectively). The current study found that tumor grade, PDCs grade, modified Dukes staging and lymphovascular invasion were independently associated with CD 44 expression (P value 0.012*, 0.046*, 0.048*, 0.022* respectively). A statistically significant association was found between both markers, ALDH1A1 and CD44 high expression in colorectal carcinoma (P value <0.001). Conclusion: ALDH1A1 and CD 44 high expression could be considered as poor prognostic marker in the evaluation of patients with Colorectal Carcinoma. Both ALDH1 and CD 44 can play essential role in the pathogenesis, aggressiveness, invasion, and progression of CRC.