Objective. Large-core needle biopsy of the breast can be performed with stereotactic or ultrasonographic guidance. However, ultrasonographically guided large-core needle biopsy has notable advantages, including the absence of ionizing radiation, increased patient comfort, and greater cost-effectiveness. The purpose of this study was to evaluate the accuracy of ultrasonographically guided large-core needle biopsy for the diagnosis of breast cancer in palpable and nonpalpable breast masses. Methods. The study was a retrospective review of consecutive ultrasonographically guided large-core needle biopsies for indeterminate breast masses. A total 424 ultrasonographically guided core biopsies were performed in 367 patients with 1 or more breast masses. Ultrasonographically guided core biopsy was performed with a 14-gauge spring-loaded needle and a freehand technique. Correlation of ultrasonographically guided core biopsy pathologic findings with subsequent surgical pathologic findings or long-term imaging followup was performed. Results. Of 424 indeterminate breast lesions for which histopathologic findings were obtained by ultrasonographically guided core biopsy, 234 cancers were diagnosed. Twenty-eight additional lesions had either questionable but not definitively malignant pathologic features (n = 11) or radiologic-pathologic discordance (n = 17) and were surgically excised. Of these, 8 additional cancers were diagnosed. Patients or surgeons chose excision of 41 additional lesions that were benign on ultrasonographically guided core biopsy. No cancer was found in these surgical specimens. One additional cancer was diagnosed at a 6-month imaging follow-up because of interval growth. On the basis of surgical and long-term imaging follow-up, the sensitivity of ultrasonographically guided core biopsy for the diagnosis of breast carcinoma was 99.2% (95% confidence interval, 95.6%-99.9%) in 173 palpable breast masses and 93.2% (95% confidence interval, 87.1%-97%) in 251 nonpalpable masses. In cancers diagnosed on the basis of immediate surgical excision as a result of ultrasonographically guided core biopsy that showed either questionable pathologic features or radiologic-pathologic discordance, the sensitivity of ultrasonographically guided core biopsy for the diagnosis of breast cancer was 99.2%. Conclusions. Ultrasonographically guided large-core needle biopsy is a sensitive percutaneous biopsy method for the diagnosis of breast cancer in palpable and nonpalpable breast masses.