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The aim of this study was to differentiate malignant and benign solid breast lesions with a novel ultrasound (US) technique, which measures speed of sound (SoS) using standard US transducers and intrinsic tissue reflections and scattering (speckles) as internal reference.This prospective, institutional review board–approved, Health Insurance Portability and Accountability Act-compliant prospective comparison study was performed with prior written informed consent from 20 women. Ten women with histological proven breast cancer and 10 with fibroadenoma were measured. A conventional US system with a linear probe was used for SoS-US (SonixTouch; Ultrasonix, Richmond, British Columbia, Canada). Tissue speckle reflections served as a timing reference for the US signals transmitted through the breasts. Relative phase inconsistencies were detected using plane wave measurements from different angular directions, and SoS images with 0.5-mm resolution were generated using a spatial domain reconstruction algorithm. The SoS of tumors were compared with the breast density of a larger cohort of 106 healthy women.Breast lesions show focal increments ΔSoS (meters per second) with respect to the tissue background. Peak ΔSoS values were evaluated. Breast carcinoma showed significantly higher ΔSoS than fibroadenomas ([INCREMENT]SoS > 41.64 m/s: sensitivity, 90%; specificity, 80%; area under curve, 0.910) and healthy breast tissue of different densities (area under curve, 0.938; sensitivity, 90%; specificity, 96.5%). The lesion localization in SoS-US images was consistent with B-mode imaging and repeated SoS-US measurements were reproducible.Using SoS-US, based on conventional US and tissue speckles as timing reference, breast carcinoma showed significantly higher SoS values than fibroadenoma and healthy breast tissue of different densities. The SoS presents a promising technique for differentiating solid breast lesions.