Post-operative management of differentiated thyroid cancer (DTC) often involves administration of radioactive iodine (RAI) for remnant ablation or adjuvant therapy. However, given the favorable prognosis associated with DTC, the risk versus benefit ratio of RAI remains unclear. RAI is associated with substantial, albeit rare side effects, including a possible increased risk of secondary malignancy and altered fertility, which must be balanced against the magnitude of benefit for decreasing recurrence and improving survival. J. Surg. Oncol. 2013;107:665–672. © 2012 Wiley Periodicals, Inc.