Abstract There is little evidence of an association between peripheral enhancement on contrast-enhanced ultrasound and histopathologic prognostic factors in breast cancer. The purpose of our study was to investigate the relationship of peripheral enhancement on contrast-enhanced ultrasound with microvessel density, vascular endothelial growth factor (VEGF) expression and other prognostic factors in patients with breast cancer. In 51 patients with BI-RADS (Breast Imaging Reporting and Data System) category 5 lesions scheduled for surgery, contrast-enhanced ultrasound with an 8-4 linear transducer and B-mode pulse inversion harmonic imaging was performed after administration of SonoVue. Forty-three histologically confirmed breast cancers were included in the study and divided into the peripheral enhancement group and non-peripheral enhancement group on the basis of their features on contrast-enhanced ultrasound. The ratio of peripheral to central microvessel density, VEGF expression, tumor size, histopathologic type, stage, lymph node metastasis and expression of estrogen receptor, progesterone receptor, c-erb-B2 and p53 were compared between the two groups. The ratio of peripheral to central microvessel density and a peripherally positive/centrally negative VEGF expression pattern were significantly higher in the peripheral enhancement group than in the non-peripheral enhancement group (t-test, p = 0.023, and χ2 test, p = 0.035, respectively). There were no significant differences in breast cancer size, histopathologic type, stage, lymph node metastasis or expression of estrogen receptor, progesterone receptor, c-erb-B2 and p53 between the two groups (χ2 test, p = 0.416, 0.877, 0.543, 0.124, 0.453, 0.554, 0.350 and 0.479 respectively). The peripheral enhancement pattern of breast cancer on contrast-enhanced ultrasound may be valuable in the evaluation of peripheral/central tumor angiogenesis and VEGF expression.