The distinction between breast cancer and benign breast diseases with nipple discharge remains an important diagnostic challenge. The purpose of this study was to predict the potential usefulness of tumor markers in nipple discharge and to investigate the relationship of tumor markers and clinical characteristics with breast cancer.One hundred and eleven patients with nipple discharge received breast surgery from November 2013 to December 2014 were included in the study. We evaluated levels of five tumor markers (CEA, CA153, CA199, CA724 and AFP) prior to treatment. Patients were divided into two groups according to postoperative pathological results: 30 cases in breast cancer group and 81 cases in benign group. The relationships of clinical characteristics with breast cancer were investigated by multivariate analysis with a logistic regression model.It showed significant differences in levels of nipple discharge CEA (P < 0.001) and CA153 (P = 0.014), but not CA199 (P = 0.856), CA724 (P = 0.171), AFP (P = 0.834) among two groups. Logistic regression analysis demonstrated complaint, age, menopause, abnormal palpable mass, CEA and CA153 were associated with breast cancer. In summary, measurements of CA199, CA724 and AFP in nipple discharge are not of great clinical value. Detecting CEA and CA153 in nipple dischargecould potentially be used for the early detection of breast cancer with in high-risk populations.