Background: Biopsy is a critical step in the diagnosis of musculoskeletal malignancy. As an alternative to open biopsy, percutaneous core needle biopsy techniques have been developed. As many studies combine office-based, image-guided, and operative biopsies, the accuracy of office-based core needle biopsy is not well documented. Question/purposes: We asked whether (1) office-based core needle biopsy for the diagnosis of malignant musculoskeletal neoplasms would have few complications and diagnostic and accuracy rates comparable to those cited in the literature for core needle biopsy, (2) diagnostic errors related to office-based core needle biopsy would result in surgical treatment errors, and (3) tissue core quantity and tumor type would affect accuracy. Patients and Methods: We retrospectively reviewed 234 patients with 252 core needle biopsies of malignant bone and soft tissue neoplasms at one institution between 1999 and 2007. Biopsy accuracy and errors were determined on the basis of histologic evaluation of prior or subsequent biopsies and/or resected specimens, when available. We eliminated 19 patients who had needle biopsies: three had the core needle biopsy completed in the operating room and 16 had insufficient documentation or followup, leaving 233 for study. Results: Of the 233 core needle biopsies, 212 (91%) were diagnostic and accurate for malignancy. Fourteen (6%) biopsies were nondiagnostic. Major errors, defined as a benign diagnosis in a malignant tumor, occurred in seven cases (3%). Minor errors, defined as errors in histopathologic diagnosis or grade, occurred in 24 biopsies (10%). All nondiagnostic and major core needle biopsy errors were identified and addressed with either a diagnostic open biopsy or definitive wide local excision, resulting in no surgical treatment errors. Accuracy was not influenced by core number; however, myxoid lesions showed a correlation with biopsy error. There were no biopsy-related complications. Conclusions: Office-based core needle biopsy for diagnosis of malignant musculoskeletal neoplasms has high diagnostic and accuracy rates without associated complications. Level of Evidence: Level II, diagnostic study. See the Guidelines for Authors for a complete description of the level of evidence.