Stereotactic X-ray mammography (SM) and ultrasound (US) guidance are both commonly used for breast biopsy. While SM provides three-dimensional (3D) targeting information and US provides real-time guidance, both have limitations. SM is a long and uncomfortable procedure and the US guided procedure is inherently two dimensional (2D), requiring a skilled physician for both safety and accuracy. The authors developed a 3D US-guided biopsy system to be integrated with, and to supplement SM imaging. Their goal is to be able to biopsy a larger percentage of suspicious masses using US, by clarifying ambiguous structures with SM imaging. Features from SM and US guided biopsy were combined, including breast stabilization, a confined needle trajectory, and dual modality imaging. The 3D US guided biopsy system uses a 7.5 MHz breast probe and is mounted on an upright SM machine for preprocedural imaging. Intraprocedural targeting and guidance was achieved with real-time 2D and near real-time 3D US imaging. Postbiopsy 3D US imaging allowed for confirmation that the needle was penetrating the target. The authors evaluated 3D US-guided biopsy accuracy of their system using test phantoms. To use mammographic imaging information, they registered the SM and 3D US coordinate systems. The 3D positions of targets identified in the SM images were determined with a target localization error (TLE) of 0.49 mm. The z component (x-ray tube to image) of the TLE dominated with a TLEz of 0.47 mm. The SM system was then registered to 3D US, with a fiducial registration error (FRE) and target registration error (TRE) of 0.82 and 0.92 mm, respectively. Analysis of the FRE and TRE components showed that these errors were dominated by inaccuracies in the z component with a FREz of 0.76 mm and a TREz of 0.85 mm. A stereotactic mammography and 3D US guided breast biopsy system should include breast compression for stability and safety and dual modality imaging for target localization. The system will provide preprocedural x-ray mammography information in the form of SM imaging along with real-time US imaging for needle guidance to a target. 3D US imaging will also be available for targeting, guidance, and biopsy verification immediately postbiopsy.