Background: External beam radiotherapy (XRT) has an established role in the management of recurrent or advanced well-differentiated thyroid carcinoma (WDTC). The goal of this study was to investigate the impact of this additional intervention on the quality of life (QOL) compared with total thyroidectomy (TT), with or without adjuvant radioactive iodine (RAI). Methods: A cross-sectional analysis using validated QOL instruments was performed. Patients receiving XRT between 1992 and 2008 for WDTC were identified and offered study participation. The Quality of Life Radiation Therapy Instrument and the Head and Neck Companion Module were administered retrospectively (N=13). For a comparison, patients previously treated with TT (N=11) alone as well as TT with postoperative RAI (N=11) for WDTC were also evaluated. Results: Thirty-four patients were included in the analysis. The XRT group reported significant decreases in chewing, swallowing, and appetite, and significant increase in pain, compared with both the RAI group and the TT group. Significant differences were reported for questions with regard to peace of mind, feeling discouraged, saliva, taste, ability to eat regular food, and concerns for the appearance of the neck in both RAI and XRT groups compared with TT patients. Subscale analysis of head and neck specific questions demonstrated significant overall differences for both RAI and XRT groups compared with thyroidectomy alone, with no differences observed between RAI and XRT groups in a direct comparison. Conclusions: RAI therapy results in a measurable decrease in head and neck specific QOL measures compared with TT alone. The addition of XRT results in additional measurable morbidity secondary to pain and dysphagia.