The rate of upgrade to cancer for breast lesions with uncertain malignant potential (B3 lesions) diagnosed at needle biopsy is highly influenced by several factors, but large series are seldom available. We retrospectively assessed the upgrade rates of a consecutive series of B3 lesions diagnosed at ultrasound- or mammography-guided vacuum-assisted biopsy (VAB) at an EUSOMA-certified Breast Unit over a 7-year timeframe. The upgrade rate was defined as the number of ductal carcinoma in situ (DCIS) or invasive cancer at pathology after excision or during follow-up divided by the total number of B3 lesions. All lesions were reviewed by one of four pathologists with a second opinion for discordant assessments of borderline cases. Excision or surveillance were defined by the multidisciplinary tumor board, with 6- and 12-month follow-up. Out of 3634 VABs (63% ultrasound-guided), 604 (17%) yielded a B3 lesion. After excision, 17/604 B3 lesions were finally upgraded to malignancy (2.8%, 95% confidence interval [CI] 1.8–4.5%), 10/17 (59%) being upgraded to DCIS and 7/17 (41%) to invasive carcinoma. No cases were upgraded during follow-up. B3a lesions showed a significantly lower upgrade rate (0.4%, 95% CI 0.1–2.1%) than B3b lesions (4.7%, 95% CI 2.9–7.5%, p = 0.001), that had a 22.0 adjusted odds ratio for upgrade (95% CI 2.1–232.3). No significant difference was found in upgrade rates according to imaging guidance or needle caliper. Surveillance-oriented management can be considered for B3a lesions, while surgical excision should be pursued for B3b lesions.