BACKGROUND Macroglossia due to amyloid depositions can cause cosmetic problems and functional disability, and can lead to life-threatening airway obstruction. Management of macroglossia in systemic amyloidosis is controversial, and the role of surgery is unclear. METHODS We present a case of a 66-year-old woman affected by macroglossia due to light chain amyloidosis who presented with eating and breathing difficulties. Because of prior successful results of radiotherapy for localized amyloid disease, our patient was treated with external beam radiation therapy (20 Gy in 10 fractions). The treatment was well tolerated by the patient. However, her systemic amyloidosis progressed, with a subclinical increase in tongue width. CONCLUSIONS This is the first reported use of radiotherapy for amyloidosis of the tongue. There was no evidence of benefit using a total dose of 20 Gy. This therapeutic modality is not recommended for the routine management of macroglossia.