The purpose of this study was to determine whether different histologic findings are obtained from different areas of breast masses seen on mammography when targeted on stereotactic breast biopsy. Twenty-one masses (mean size, 1.8 cm; range, 0.7–5.5 cm) underwent stereotactic biopsy using a 14-gauge directional vacuum-assisted biopsy probe (Mammotome, Biopsys/Ethicon Endo-Surgery, Cincinnati, OH). The central and peripheral areas of the mass were targeted and biopsied separately, and histologic findings from the targeted center and periphery were compared. Six of 21 masses (29%) were heterogeneous, yielding different histologic results from the targeted center and periphery. In 4 heterogeneous masses, which constituted 4 of 21 masses (19%) in this study, surgical biopsy was recommended on the basis of findings obtained from only the center (n = 2) or the periphery (n = 2). Stereotactic biopsy findings in these 4 masses were atypia in 3 and radial scar in 1; none of these 4 masses had carcinoma at surgery. In all 4 masses that proved to be malignant, the diagnosis of carcinoma was made in specimens obtained from both the targeted center and the periphery of the mass. Breast masses can be heterogeneous, yielding different histologic findings from different areas of the mass. Our data suggest that sampling part but not all of a mass may miss certain histologic components of the mass, but should not result in a failure to diagnose carcinoma.