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Objective: Image-guided sternal biopsy may be technically daunting given the immediately subjacent critical structures. There is a paucity of literature describing technique, safety, and efficacy. This study aims to quantify the diagnostic yield and safety of image-guided sternal biopsies. Secondary aims include (1) describing the preferred approach/technique and (2) identifying imaging features and disease entities associated with higher and lower diagnostic yields. Materials and methods: A retrospective review of 50 image-guided sternal biopsies performed at two quaternary care centers from 2000 to 2019 was performed. Recorded lesion-related variables included as follows: location, density, extraosseous extension, and size. Recorded variables from electronic medical records included as follows: patient demographics, histologic or microbiological diagnosis, and complications. Recorded technique-related variables included as follows: needle obliquity, type, and gauge; biopsy core number and length; and modality. Results: Of the 50 biopsies, 88.0% resulted in a definitive histologic diagnosis. Six biopsies were non-diagnostic. The majority of biopsies were performed under computed tomography (88.0%), followed by ultrasound (12.0%). Tumor was the most common biopsy indication (90.0%), followed by infection (10.0%). Of the diagnostic biopsies indicated for tumor, 88.9% were malignant. Seventy-four percent of the lesions were predominantly lytic. Fifty percent of lesions had extraosseous extension. Lesion locations were as follows: manubrium (48.0%), sternal body (48.0%), and sternomanubrial joint (4.0%). No minor or major, acute, or delayed procedure-related complications were encountered. Conclusion: Image-guided sternal biopsy is an efficacious and safe method of obtaining a definitive histologic diagnosis regardless of lesion-specific features or location. [ABSTRACT FROM AUTHOR]