Background: There is an actual need for novel prognostic biomarkers to improve colorectal cancer (CRC) patient’s outcome. We aim to evaluate SOX2 and EpCAM immunohistochemical expression in 40 cases of CRC and premalignant lesions. Methods: The immunohistochemical expression was done according to Envision polymer technique on 40 cases of CRC besides twenty specimens of premalignant lesions. Furthermore, their clinicopathological significance was statistically investigated. Results: High SOX2 immunoexpression was detected in 57.5 % of CRC cases and was significantly associated with tumor size, high tumor grade, LVI, LN involvement, advanced tumor stage, and tumor budding (P=0.04, P<0.001, p=0.02, p=0.001, p=0.001, p=0.001, respectively). Negative SOX2 immunoexpression was observed in 70 % of premalignant lesions with no statistically significant difference. High EpCAM immunoexpression was noted in 21 52.5% of the malignant lesions, and was significantly associated with high tumor grade, LVI, LN involvement, advanced tumor stage, and tumor budding (P=0.005, p =0.002, p<0.001, p<0.001, p=0.005, respectively). A statistically highly significant association between low and moderate EpCAM expression and stromal lymphocytic infiltration (P<0.001). Low EpCAM expression was noted in 75 % of premalignant lesions with no statistically significant difference. Conclusions: This study emphasized the role of SOX2 and EpCAM in colorectal carcinogenesis and their implication in CRC progression, LN metastasis and distant metastasis.