To assess the efficacy of contrast-enhanced mammography (CEM) in differentiating benign from malignant breast lesions in Asian patients with bloody nipple discharge (BND). This retrospective study included 58 women with BND (mean age: 51.7 years) who underwent standardized CEM at institutions in Taiwan and Singapore. Lesion characteristics (size, enhancement, conspicuity, shape, margins) were evaluated on CEM by blinded radiologists. Non-enhanced mammography (MMG) and ultrasound (US) within a defined timeframe were compared for diagnostic accuracy. Benign or malignant status was confirmed by biopsy or 2-year imaging follow-up. Malignancy was found in 29 of 58 lesions (50.0%), with ductal carcinoma in situ (DCIS) being the most common. CEM demonstrated a 100% negative predictive value (NPV) for non-enhancing lesions. Significant predictors of malignancy on multivariate analysis include enhancing lesions of size ≥ 1.5 cm (p-value 0.025) and suspicious morphological features (irregular/spiculated margins, irregular shape, segmental/linear NME distribution) (p-value < 0.001). CEM outperformed MMG (sensitivity: 58.6%) and US (sensitivity: 79.3%), achieving a sensitivity of 100% and the highest diagnostic accuracy at 81.3%. Additionally, a CEM size cut-off of 1.5 cm yielded a sensitivity of 73.5% and a specificity of 84.3%. CEM effectively differentiates benign from malignant lesions in patients with BND, improving diagnostic accuracy and potentially reducing unnecessary interventions.