Objective <p>The purpose of the present study is to determine whether or not lesion characteristics on PET/CT could reduce the number of samples required to achieve a diagnosis in image-guided bone biopsies (IGBB).</p> Materials and methods <p>A retrospective review of 38 percutaneous IGBB performed at a single center. Biopsies have been performed from January 1st, 2020, to October 23rd, 2024. Inclusion criteria were patients with a PET/CT and a histopathologic report available. Specimens were collected, numbered, and independently analyzed in separate containers. PET/CT data, including SUV_max, SUV_mean, MTV, TLG, and morphological lesion characteristics, were correlated with biopsy outcomes and subjected to statistical analysis. Patients were classified by the number of samples needed for diagnosis: first (Group 1), second (Group 2), or third/subsequent (Group 3).</p> Results <p>Thirty-four/38 (89%) involved spinal and pelvic locations (34/38; 89%). Breast cancer metastases were the most common diagnosis (21/38; 55%). Group 1 included 20 IGBB (52%), group 2 included 9 IGBB (24%), and group 3 included 9 IGBB (24%). No statistically significant difference was found between groups in metabolic characteristics and the number of samples needed for diagnostic purposes (<i>p</i> &gt; 0.05). Subgroup analysis, including factors such as density or lesion size, didn’t find any significant differences between groups.</p> Conclusion <p>The results suggest that high metabolic activity alone does not justify reducing the number of biopsy samples without compromising diagnostic performance. This supports the recommendation to obtain at least three samples and highlights the importance of selecting the safest biopsy site, regardless of metabolic activity.</p> Critical relevance statement <p>This study critically assesses the role of FDG PET/CT metabolic parameters in predicting the diagnostic success of IGBB, providing new insights to improve target selection and biopsy planning in clinical radiology.</p> Key Points <p><UnorderedList Mark="Bullet"> <ItemContent> <p>This study assessed whether metabolic activity on FDG PET/CT influences the diagnostic yield of IGBB.</p> </ItemContent> <ItemContent> <p>High metabolic activity did not allow for reducing the number of samples without affecting diagnostic performance.</p> </ItemContent> <ItemContent> <p>At least three biopsy samples should be obtained, prioritizing safety over metabolic activity when selecting the biopsy site.</p> </ItemContent> </UnorderedList></p> Graphical Abstract <p></p>