Objective: To investigate CD74 expression in invasive ductal carcinoma (IDC) of the breast and its clinical significance. Methods: The CD74 expression along with the expressions of estrogen receptor (ER), progesterone receptor (PR) and c-erbB-2 in 45 IDC tissues were determined by immunohistochemical staining, and then the relations of CD74 expression with the expressions of ER, PR and c-erbB-2 as well as with the clinicopathologic profiles and prognosis of the patients were analyzed. CD74 expression in three breast cancer cells that were MB-MDA-435 cells (highly invasive), MCF-7 cells (low invasive) and CD74 expression plasmid transfected MCF-7 cells were observed, and then the invasion abilities of the three cells were tested by Transwell assay. Results: In IDC, CD74 expression level was significantly related to pathologic grade of IDC, which was the poorer the differentiation of cancer cells, the higher was the expression of CD74; the CD74 expression rate in receptor-positive group was significantly lower than that in receptor-negative group; the expression rate of CD74 in triple-negative breast cancer was significantly higher than that in non-triple-negative breast cancer; the rate of lymph node metastasis in CD74 positive patients was higher than that in CD74 negative cases; CD74 expression was not related to 5-year survival rate of patients. CD74 expression intensity in highly invasive MB-MDA-435 cells was significantly higher than that in low invasive MCF-7 cells, while the invasive ability of MCF-7 cells was increased after transfection with CD74 expression plasmid. Conclusion: CD74 may play an important role in invasion and lymph node metastasis of breast cancer, and it may also be a potential marker for high invasive breast cancer, especially the triple-negative breast cancer.