Objective To explore the value of three-dimensional contrast-enhanced ultrasound angiography in the differential diagnosis of breast masses. Methods A total of 120 patients with breast masses who were treated in our hospital from July 2013 to February 2016 were selected as the research objects retrospectively, including 70 patients of benign tumor (benign group) and 50 patients of malignant tumor (malignant group) that confirmed by surgery and pathology. All patients were given conventional two-dimensional ultrasound and three-dimensional contrast-enhanced ultrasound angiography during the diagnosis. Compared the imaging features of benign group and malignant group, and compared the diagnostic value of two-dimensional ultrasound and three-dimensional contrast-enhanced ultrasound angiography for breast masses. Results Compared with benign group, the rates of irregular masses, unclear boundary, inhomogeneous echo, lateral shadowing, echo attenuation, and micro calcification in the malignant group were all higher (P<0.05). The three-dimensional contrast-enhanced ultrasound angiography scores in malignant group and benign group were significantly different with each other (P<0.05), the score of the malignant group was higher than that of benign group. The 2- and 3-score was common in benign group, but 4- and 5-score was common in malignant group. The diagnostic sensitivity of two-dimensional ultrasound and three-dimensional contrast-enhanced ultrasound angiography for breast masses were 97.1% (68/70) and 98.6% (69/70) respectively, and the specificity were 80.0% (40/50) and 96.0% (48/50) respectively, the specificity of three-dimensional contrast-enhanced ultrasound angiography was significantly higher than that of two-dimensional ultrasound (P<0.05). Conclusion Two-dimensional ultrasound and three-dimensional contrast-enhanced ultrasound angiography both have a certain diagnostic value in the differential diagnosis of breast masses, but the three dimensional contrast-enhanced ultrasound angiography can get more information through assessment of richness of the microvascular in tumor tissue, so as to improve the diagnostic specificity and is worthy of popularization and application.