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To retrospectively evaluate the safety and efficacy of percutaneous image-guided mediastinal mass core-needle biopsy. Retrospective review of an institutionally maintained biopsy registry identified 337 computed tomography- or ultrasound-guided percutaneous mediastinal mass core needle biopsies between October 2002 and August 2017 in a single quaternary referral center. Mean patient age was 51 (range, 18 to 93) years. Procedural techniques, anticoagulation/antiplatelet therapy, and tumor anatomical characteristics were reviewed. Classification and g