Systemic amyloidosis is an unusual cause of mediastinal lymphadenopathy. Thoracic surgeons are often called upon to establish a diagnosis in patients with mediastinal lymphadenopathy, so familiarity with mediastinal amyloidosis is valuable. We report our experience with 2 patients, and discuss the diagnostic role of mediastinoscopy and other less invasive biopsy techniques. General anesthesia may pose significant risks in this disease; nonoperative biopsy techniques should be considered if the diagnosis of amyloidosis is suspected.