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Current methods to predict the outcome for patients with curatively resected colorectal cancer (CRC) are not ideal. The combined use of molecular markers and clinicopathologic features may be better to identify patients with a poor prognosis. CD74 expression has been suggested to be a poor prognostic factor with a higher relative expression in many cancers. The p53 gene mutation is closely related to carcinogenesis in most malignant tumors. This study aimed to evaluate the prognostic value of CD74 and p53 expressions in CRC in relation to clinicopathologic parameters including the density of tumor-infiltrating lymphocytes.We used immunohistochemistry to determine the expression of CD74 and p53 in primary tumor samples from 48 patients with CRC. The associations between their expression and clinicopathological variables were assessed.CD74 staining was positive in 68.75% of the studied cases. CD74 expression showed significant associations with poorly differentiated tumors (P=0.16), depth of tumor invasion (P=0.14), the presence of nodal metastasis (P=0.04), and advanced stage (P=0.01). There was a negative relation between CD74 expression and the density of tumor-infiltrating lymphocytes (P=0.22). p53 staining was positive in 29 of 48 specimens (60.42%). There were significant relations between p53 expression and pathological variables such as tumor grade (P=0.017) and depth of tumor invasion (P=0.025). p53 expression was associated significantly with positive nodal metastasis (P=0.01) and stage III cases (P=0.024).CD74 and p53 could serve as poor prognostic indicators in patients with CRC. CD74 expression was inversely related to tumor infiltrating lymphocytes suggesting that CD74 is involved in immune escape process.