Core needle biopsy is a powerful tool used to diagnose and develop a treatment strategy for musculoskeletal tumors. With accuracy rates reported between 69% and 99%, it is evident that errors in diagnosis occur, and they can lead to devastating consequences. We reviewed pathology reports of preoperative core needle biopsies in an attempt to determine factors associated with false negative diagnoses for the purpose of improving surgical planning. We retrospectively reviewed all office-based core needle biopsies accomplished in our practice over a 6-year period. One hundred nineteen biopsies were identified, of which 82 fulfilled criteria to be included in the study population. The pathologist's report of each biopsy was reviewed and categorized based on the findings into 1 of 2 diagnostic groups: neoplastic or nonneoplastic. The results of the biopsies were then compared to the pathology results of the final surgical resection, and the rates and nature of false negative biopsy results (unrecognized malignant pathology) were compared for each group. Seventy-one biopsies were categorized as neoplastic based on the pathology report. No false negative results were found in this group when compared to the final surgical resection pathology. Eleven biopsies were categorized as nonneoplastic, of which 6 were found to be false negatives when compared to the final surgical pathologic diagnosis. The rate of false negative results significantly increased in biopsies whose reports were categorized as nonneoplastic compared to biopsies categorized as neoplastic (P<.0001). We found core needle biopsies of musculoskeletal lesions to be safe and effective in diagnosing pathologic processes. In cases in which analysis of the biopsy specimen did not identify a specific neoplastic process, we found a high incidence of undiagnosed malignancy upon definitive surgical resection. Pathology reports of core needle biopsies that specify only normal, inflammatory, or other nonspecific tissue descriptions should alert the clinician to the increased possibility of a false negative result, and require further tissue analysis.