The efficacy of image-guided vacuum-assisted biopsy (VAB) was investigated to correctly determine a pathologic complete response in the breast (pCR-B). In up to 80% of women with breast cancer, neoadjuvant systemic therapy (NST) results in a pathologic full response. Breast surgery, which was the gold standard for verifying pCR-B, may be deemed overtreatment in such circumstances. The prospective, multicenter study involved 452 women with stage 1-3 breast cancer of all biological subtypes. About 54 women were left out, leaving 398 women in the study. Before undergoing guideline-adherent breast surgery, all subjects had an imaging-confirmed partial or complete response to NST and received study-specific image-guided VAB. The VAB-confirmed pCR-B false-negative rate (FNR) was the primary outcome. In 37 of 208 women, image-guided VAB alone failed to detect surgically proven residual tumors [FNR, 17.8%; 95% CI, 12.8–23.7%]. 12 (32.4%) of the 37 women had only residual DCIS, 20 (54.1%) had a minor residual tumor (<5 mm), and 19 of the 25 (76.0%) had invasive cancer cellularity of less than or equal to 10%. The false-negative result might have been avoided in 19 of the 37 cases (51.4%). Using the most giant needle by volume (7-gauge) for VAB resulted in no false-negative results. Integrating imaging and image-guided VAB into a single diagnostic test reduced the FNR to 6.2% (95% CI, 3.4% –10.5%). Image-guided VAB had a higher rate of missing residual disease than expected. Before abandoning breast surgery, refinements in process and patient selection were conceivable and necessary.