Abstract: The incidence of thyroid cancer is steadily rising, with differentiated thyroid cancer (DTC) accounting for most cases. While standard treatment offers a good prognosis for most DTC patients, a small subset experiences resistance to radioactive iodine during ¹³¹I therapy. This resistance is characterized by a lack of iodine uptake in lesions or continued disease progression, defined as radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC). Patients with RAIR-DTC face a significantly poorer prognosis and increased mortality. Several factors influence the prognosis of patients with RAIR-DTC, including age, tumor characteristics, genetic alterations, serum biomarkers, imaging findings, and different treatment modalities. This article provides a comprehensive overview of the outcomes and prognostic factors associated with RAIR-DTC, aiming to provide assistance in timely evaluating the survival expectations of RAIR-DTC patients and guiding clinical decision-making.