Objective: To explore the clinicopathological characteristics of 6 cases of primary breast carcinoma with signet-ring cell differentiation. Methods: Six cases of primary breast carcinoma with signet-ring cell differentiation were studied with histopathological and immunohistochemical staining, and its clinical and pathological findings were analyzed with review of the literature. Results: All the patients were female, with the average age of 45 years. All the patients presented with a lump in the breast. The histological examination of the neoplastic cells showed that the majority of tumor cells showed features of signet-ring cells. They were small and round, scattered or funicular distribution, and with large intracytoplasmic mucin compressing the nuclei toward one pole of the cell. Three of the six cases were pure signet-ring cell carcinoma, and three were mixed with other subtypes of invasive breast carcinoma. Immunohistochemically, the tumor cells in 5 of the 6 cases were focally positive for ER, and 3 of 6 cases were focally positive for E-Cadherin. One of 6 cases have the positive status of Her-2 (3+), 2 of them with Her-2 (2+), and 3 of them with Her-2 (1+). Five of the six cases had lymph node metastases. Five cases were treated with modified radical mastectomy, and 1 case with mastectomy alone. Two of the six cases occurred distant metastasis after 3 and 4 years respectively. All the cases survived after the last follow-Up. Conclusion: The diagnosis of primary breast carcinoma with signet-ring cell differentiation is based on distinctive histopathology and immunohistochemical staining. Compared with other subtypes of invasive breast carcinoma, primary breast carcinoma with signet-ring cell differentiation exhibits higher invasiveness and worse prognosis.