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Introduction: Biopsy of the musculoskeletal system is useful in the management of bone lesions particularly in oncology but they are often challenging procedures with a significant risk of complications. Computed tomography (CT)-guided needle biopsies may decrease these risks but doubts still exist about their diagnostic accuracy. This retrospective analysis of the experience of a single institution with percutaneous CT-guided biopsy of musculoskeletal lesions evaluates the results of these biopsies for bone lesions either in the appendicular skeleton or in the spine, and defines indications. Materials and methods: We reviewed the results of 2027 core needle biopsies performed over the past 18 years at the authors' institution. The results obtained are subject of this paper. Results: In 1567 cases the correct diagnosis was made with the first CT-guided needle biopsy (77.3% accuracy rate), in 408 cases the sample was not diagnostic and in 52 inadequate. Within 30 days these 408 patients underwent another biopsy, which was diagnostic in 340 cases with a final diagnostic accuracy of 94%. Highest accuracy rates were obtained in primary and secondary malignant lesions. Most false negative results were found in cervical lesions and in benign, pseudotumoral, flogistic, and systemic pathologies. There were 22 complications (18 transient paresis, 3 haematomas, 1 retroperitoneal haematoma) which had no influence on the treatment strategy, nor on patient outcome. Conclusion: This technique is reliable and safe and should be considered nowadays the gold standard for biopsies of the musculoskeletal system.