Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among females. However, mammographic diagnosis is sometimes non-conclusive with a Breast imaging Reporting and Data System (Bi-RaDS) result of 0. Cancer antigen 15-3 (CA15-3) is the most widely used serum tumor marker for breast cancer screening. Platelet distribution width (PDW) is an early indicator of platelet activation. Fibrinogen contributed to angiogenesis and distant metastasis. The aim of this study was to investigate the ability of CA15-3, PDW, and fibrinogen individually or in combination, to distinguish breast cancer from benign breast disease. 200 consecutive patients with breast cancer and 187 patients with benign breast disease were included in this retrospective study. Patients' characteristics and hematologic tests data at initial diagnosis were collected. The benefit of adding PDW and fibrinogen to a model with only CA15-3 was evaluated as an increased in the area under the curve (AUC) obtained by receiver operating curve (ROC). CA15-3, PDW and fibrinogen are higher in breast cancer patients than in patients with benign breast disease. Single biomarkers had AUC values ranging from 0.687 for fibrinogen to 0.810 for CA15-3. In addition, the combination of PDW, CA15-3, and fibrinogen increased the AUC to 0.900 (0.866-0.928) (p<0.0001), significantly higher than those of any single marker. In conclusion, the combined use of CA15-3, PDW and fibrinogen may be clinically useful in discriminating between breast cancer and benign breast disease in non-conclusive mammography patients.