Amyloidosis is a disease related to abnormal protein folding and deposition of that abnormal protein between cells of the body in various tissues and organs, resulting in multiple clinical manifestations. We report a case of amyloidosis with atypical features, isolated to the mediastinum, in a 75-year-old male who presented with fatigue and shortness of breath. Amyloidosis that is isolated to the mediastinum without pulmonary parenchymal involvement is exceptionally rare. It has been hypothesized that localized mediastinal amyloidosis manifesting as amyloidomas is a distinct clinical subtype with a better prognosis than classic systemic amyloidosis. This paper describes the radiologic features of localized mediastinal amyloidosis (along with its pathologic correlation) and compares systemic and isolated disease.