The purpose of this study was to evaluate the safety, technical success rate, and diagnostic efficacy of drill-assisted axial and appendicular bone biopsies. During a 3-y period, 703 drill-assisted biopsies were performed. The cohort included 54.2% men, with a mean age of 57.6 y ± 17.1. Median lesion volume was 10.9 mL (interquartile range, 3.4–30.2 mL). Lesions were lytic (31.7%), sclerotic (21.2%), mixed lytic and sclerotic (27.7%), or normal radiographic bone quality (19.3%). No complications were reported. The technical biopsy success rate was 99.9%. Crush artifact was present in 5.8% of specimens submitted for surgical pathologic examination, and 2.1% of specimens were inadequate for histologic evaluation.