PURPOSE: The purpose of this study was to compare the value of contrast-enhanced ultrasound (CEUS) plus MicroFlow Imaging (CEUS-MFI), MicroFlow Imaging (MFI) alone, and color Doppler flow imaging (CDFI) in the differential diagnosis of benign and malignant breast lesions. METHODS: A total of 116 patients with 116 breast lesions categorized as Breast Imaging Reporting and Data System (BI-RADS) category 4 were enrolled in this prospective study. CEUS-MFI, MFI, and CDFI were used to evaluate the microvascular morphology and distribution types of breast lesions. Pathological results were considered the gold standard. RESULTS: Compared with conventional CDFI and MFI, the CEUS-MFI technique can reveal microvasculature and distribution types at a higher resolution in breast masses. The sensitivity, specificity, and accuracy of CEUS-MFI were 96.3%, 80.6%, and 91.4%, respectively. The sensitivity, specificity, and accuracy of MFI were 87.5%, 75.0%, and 83.6%, respectively. The sensitivity, specificity, and accuracy of CDFI were 58.8%, 72.2%, and 62.9%, respectively. The accuracy was significantly different between CEUS-MFI and MFI (P = 0.024), and the accuracy was significantly different between CEUS-MFI and CDFI (P = 0.000). US BI-RADS 4A masses were downgraded based on CEUS-MFI features without any malignancy missed, with the biopsy rate decreasing from 100% (29/29) to 31.0% (9/29). CONCLUSION: CEUS-MFI provides improved diagnostic efficacy for breast lesions. The CEUS-MFI technique can be used as an effective supplement to conventional ultrasound in the diagnosis of breast tumors.