OBJECTIVE To retrospectively evaluate the safety and efficacy of percutaneous image-guided mediastinal mass core-needle biopsy. METHODS 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 gradation of complications was based on the Clavien-Dindo system. Diagnostic yield was defined as the ratio of diagnostic biopsy to all biopsies performed. RESULTS Mean tumor size was 59.2 (range, 10 to 180) mm with 89.9% (n=303) of lesions located in the prevascular (anterior) mediastinum. There was a single major complication (0.3%) of a symptomatic pneumothorax requiring intervention. There were seven (2.1%) minor complications, including three bleeding complications. A transpleural approach was the only variable associated with an increased complication rate (P<.01). Forty-one (12.2%) patients had a biopsy performed while taking an antiplatelet/anticoagulant agent within the therapeutic window, with a single case (0.3%) associated with a minor bleeding complication. Of 18 (5.3%) procedures performed without cessation of anticoagulant/antiplatelet therapy, there were no bleeding complications. Of all 337 biopsies, 322 (95.5%) were diagnostic. None of the analyzed variables were significantly associated with a nondiagnostic biopsy. CONCLUSIONS Image-guided percutaneous core-needle biopsy of mediastinal masses is a safe procedure with high diagnostic yield. Further prospective studies are required to assess the complication profile in higher risk patients.