Radioiodine has served an important role in the diagnostic workup and treatment of patients with differentiated thyroid cancer for more than 6 decades. The interpretation of radioiodine scintigraphic studies should be performed in conjunction with a comprehensive history, histopathologic correlation, and pertinent laboratory values, as well as correlation with available anatomic images and the findings from physical examination. A thorough understanding of the physiology and biodistribution of radioiodine is critical when interpreting radioiodine scintigraphic studies to avoid misinterpretation of physiologic and nonthyroid pathologic variants as thyroid cancer metastases. Differentiating a false-positive finding from a true metastasis on pretherapy radioiodine scintigrams is important to determine the appropriate radioiodine treatment dose. The correct interpretation of posttherapy radioiodine scintigraphic studies is also important to determine if repeat radioiodine treatment will be necessary and for the future clinical and imaging followup of the patient. A variety of different factors, such as the presence of the sodium-iodide symporter and the passive diffusion or retention of radioiodine in normal and pathologic structures, can result in false-positive results on radioiodine scintigrams. Numerous false-positive findings have been reported in the literature and are further demonstrated with the increasing availability of single photon emission computed tomography (SPECT) integrated with computed tomography (CT) as true dual-modality imaging (SPECT/CT). SPECT/CT has been documented to be of incremental value in the accurate anatomic localization and characterization of radioiodine uptake as false-positive findings, particularly in cases with discordant findings of a low serum thyroglobulin level but positive findings on radioiodine whole-body planar scintigrams. The objectives of this review are to describe the physiology and biodistribution of radioiodine and to provide examples of false-positive results on radioiodine scintigrams, with clinical and anatomic correlation, in the following categories of radioiodine uptake: functional uptake secondary to sodium-iodide symporter expression, radioiodine retention, nonthyroid neoplasms, inflammatory or infectious uptake, contamination, and other causes. ©RSNA, 2017.