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131I whole-body scintigraphy (WBS) is a highly sensitive method for the detection of differentiated thyroid tumors and metastases. However, a lack of anatomic landmarks and the physiologic accumulation of the tracer complicate interpretation of the images. This prospective study was designed to evaluate the incremental value of 131I SPECT/CT over planar WBS in the management of patients with differentiated thyroid carcinoma (DTC). Methods: Planar imaging was performed on 66 consecutive DTC patients who were considered to have locally advanced or metastatic disease after total or nearly total thyroidectomy. SPECT/CT was added for patients whose planar findings were inconclusive. The planar images were interpreted by 2 experienced nuclear medicine physicians. Interpretation of the SPECT/CT images was a consensus opinion of one of the nuclear medicine physicians and an experienced radiologist. Fusion images were considered to improve image interpretation when they better localized sites of increased 131I uptake. The final diagnosis was verified by pathologic findings, other imaging modalities, and clinical follow-up. Both site-based and patient-based analyses were performed, and the impact of SPECT/CT results on therapeutic strategy was assessed. Results: A total of 232 foci were observed by 131I WBS, including 33.2% of foci localized in the thyroid bed, 62.1% due to malignant lesions, and 4.7% caused by nonthyroidal physiologic or benign uptake or a contaminant. Overall, 37 SPECT/CT studies were performed on 23 patients, whose planar images showed 81 inconclusive lesions. Precise localization and characterization of 131I-avid foci were achieved through 131I SPECT/CT in 69 (85.2%) and 67 (82.7%) of the 81 foci, respectively. Fusion images were considered to be of benefit in 17 (73.9%) of 23 patients. The therapeutic strategy was changed in 8 (47.1%) of 17 patients. Uncommon metastatic lesions were found in 9 (13.6%) of 66 patients with regard to SPECT/CT fusion images. Conclusion: Fusion of SPECT and CT images was of incremental value over WBS in increasing diagnostic accuracy, reducing pitfalls, and modifying therapeutic strategies in 73.9% of DTC patients. As SPECT/CT techniques emerge, 131I SPECT/CT may demonstrate higher value than WBS in the management of DTC.