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Conventional smear cytology (CSC) is a specific method used for breast tumor diagnosis in patients with nipple discharge. However, CSC tends to miss diagnose or even misdiagnose due to contaminating blood cells and other impurities. Thus, it is critical to develop more accurate and sensitive methods for clinical evaluation. Using nipple discharge collected directly from patients without aspiration, we performed liquid-based cytology (LBC) to analyze 111 collected samples for cytological evaluation for the first time. Following centrifugation to remove blood cells and protein contaminants, the sample of each nipple discharge was analyzed by light microscopy. In parallel, CSC was performed for comparison. Our results showed LBC has better diagnostic sensitivity than CSC (40.00% vs. 22.22%, = 6.636, P = 0.01). The specificity was improved (LBC 100% vs. CSC 95.2%) and area under the curve was also enhanced (AUCLBC=0.700 vs. AUCCSC=0.587). Moreover, LBC images have a cleaner background, clearer field of view, uniform cell arrangement, and improved colour contrast, with an overall image quality significantly better than CSC. Therefore, LBC provides a new and better diagnostic method for early detection of breast tumors with nipple discharge. [ABSTRACT FROM AUTHOR]