To evaluate the role of multiparametric ultrasound (mpUS) in the characterization of focal breast lesions (FBLs). This prospective study enrolled patients undergoing multiparametric breast ultrasound for FBLs. An experienced breast radiologist evaluated the following ultrasound features: US BI-RADS category, vascularization pattern (internal, vessels in rim and combined) and presence of penetrating vessels with each Doppler method (Color-Doppler, Power-Doppler, Microvascular imaging), strain ratio (SR) and Tsukuba score (TS) with Strain Elastography (SE), Emax, Emean, Emin and Eratio with 2D-shear wave elastography (2D-SWE). Core biopsy for all BI-RADS 4-5 FBLs and 24-month follow-up for all BI-RADS 2-3 FBLs were considered for standard of reference. The diagnostic performance was assessed with the area under curve (AUCs) and cut-off values were determined according to the Youden's index. A total of 139 FBLs were included with 75/139 (53.9%) benign and 64/139 (46.1%) malignant FBLs. Internal vascularization patterns (p < 0.001), penetrating vessels (p < 0.001), TS 4-5 (p < 0.001) and all 2D-SWE parameters (p < 0.001) were significantly different between benign and malignant FBLs. The BI-RADS score provided an AUC of 0.876 (95% CI 0.810-0.926) for the diagnosis of malignant FBLs. Among the 2D-SWE measurements, an excellent diagnostic performance was observed for Emax with an AUC of 0.915 (95% CI 0.856-0.956) and Emean of 0.908 (95% CI 0.847-0.951). Optimal cutoff for the diagnosis of malignant FBLs were US BI-RADS > 3, Strain Ratio > 2.52, Tsukuba Score > 3, Emax > 82.6kPa, Emean > 66.0kPa, Emin > 54.4kPa and Eratio > 330.8. Multiparametric ultrasound, particularly SWE, can improve specificity in the characterization of FBLs.