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Abstract Purpose This case series explores the utility of positron emission tomography (PET)/computed tomography (CT) guidance for biopsy of 18F-fludeoxyglucose (FDG)-avid osseous lesions that are inconspicuous on CT. Methods PET/CT-guided core biopsies were performed in four patients with suspected malignancies given 18F-FDG-avid osseous lesions that were inconspicuous on CT alone. The final diagnosis for each patient was determined by histopathological and molecular testing. Results PET/CT-guided biopsy yielded accurate sampling via core needle biopsy (CNB) with histopathological confirmation of osseous metastases of the primary malignancy as opposed to a secondary malignancy in three patients and ruled-out metastatic spread in the fourth. Conclusion PET/CT-guided biopsy of hypermetabolic osseous lesions that are inconspicuous on CT alone is an effective and safe diagnostic tool in patients with suspected malignancy.