Objective: To determine the efficacy of ultrasound-guided vacuum-assisted percutaneous excision technique in treating non-palpable breast lesions. Materials and Methods: Between January 2012 and November 2014, a total of 452 non-palpable breast lesions diagnosed by ultrasonography in 400 patients were treated by ultrasound-guided vacuum-assisted percutaneous excision. All patients received pressure dressings, which were removed after 48 hours, then rechecked after three months. Results: Ultrasonography clearly displayed all 452 breast lesions during the mammotome biopsy. The operative process was successfully guided. All patients were free from infections or pneumothoraces, as well as skin lesions; four patients developed postoperative local hematomas and five patients had local bruising. The incidence of local hematomas was 6.0% (27/452). One mass residue was detected during the ultrasonographic follow up after three months. Conclusion: Ultrasound-guided vacuum-assisted percutaneous excision for non-palpable breast lesions has advantages, including simple operation, accurate positioning, safety, minimal invasion, fewer complications, rapid recovery, and good cosmetic appearance. It can substitute the traditional surgical approach and is thus recommended as an alternative minimally invasive technique.