The purpose of this study was to determine the false negative rate of stereotactically guided vacuum biopsy (VB). Data of patients with benign lesions in VB were evaluated retrospectively during a median follow-up period of 21 months. A total of 404 VB were considered benign and representative and were recommended for follow-up. Of these 404 lesions, 195 were completely removed radiologically. Follow-up data were available for 354/404 patients (87.6%), with intervals ranging from 3 to 66 months (median 21, mean 22.4). Reintervention or surgery was necessary in 13/354 (3.7%) cases. Of these cases, 5/354 (1.4%) turned out to be false negatives. Four of these cases showed large areas of microcalcifications or several clusters, and only partial removal was possible due to the size of the lesions. Although VB is an accurate procedure for diagnosing nonpalpable breast lesions with a low cancer miss rate, we consider the exclusion of malignancy in cases of disseminated microcalcifications or several clusters as a limitation. The radiologic-pathologic correlation in these cases is a challenge, particularly in terms of the residuals. Strict follow-up of benign lesions is essential to avoid delayed cancer diagnosis.