Background and Aims: In the following study case, we reviewed breast ultrasound-guided core needle biopsy (CNB), using Mammotome (vacuum-assisted breast biopsy) and Tru-cut, carried out on palpable and nonpalpable uncertain breast lumps or malignant large lesions to be submitted to neoadjuvant chemotherapy. Material and Methods: Examinations were conducted during a 4-year period of clinical activity in a highly specialized center, from December 2009 to December 2013, in 712 patients previously subjected to fine-needle aspiration cytology (FNAC). Results: The results demonstrated that among the 712 breast biopsies, in many cases FNAC was not conclusive, and therefore we proceeded with the echo-guided biopsy, through which we were able to collect sufficient material for the histological examination in order to direct patients to surgery or follow-up. Conclusions: CNB is far superior to FNAC, especially in cases of uncertainty, where it is preferable to proceed directly with CNB, which may also determine additional prognostic and predictive markers. Initially FNAC is less expensive, but the actual costs involved tend to be higher for FNAC as it is less accurate and a CNB is often required. In accordance with recent publications, we can confirm the full validity of CNB in the diagnostic approach of breast lesions.