Background: The most prevalent endocrine cancer is differentiated thyroid carcinoma, which accounts for 80%–90% of all thyroid malignancies as the most prevalent histologic subtype. Objective: To evaluate the role of F18-FDG PET/CT in the prognosis and diagnosis of cases with differentiated thyroid cancer who have high thyroglobulin levels and negative I131 WBS. Materials and methods: This prospective study was conducted on 52 patients with pathologically proven differentiated thyroid carcinoma. Those patients were under follow-up at Al Kasr Alaieny Hospital, Cairo University, between May 2018 and December 2020. We reviewed those patients; all patients had persistently elevated Tg levels after total thyroidectomy and remnant ablation with RAI, with no thyroid residual tissue. The patients' follow-up was done by measuring stimulated thyroglobulin level and anti-TG level, neck U/S, and DXWBS. Patients presenting no radiological evidence of recurrence and elevated Tg values, are included for studying FDG-PET/CT was performed. Results:  The sensitivity and specificity of FDG PET/CT were 92% and 72% respectively compared to 43% and 71% for I131 WBS. SUVmax cutoff point was at 1.5. On the other hand, DX WBS using I131 had sensitivity and specificity of 43% and 71% respectively. Patients with lesions attaining avidity for both iodine and FDG have better OS than those with lesions avid for FDG and lost iodine avidity. Conclusion: FDG PET/CT provides additional information in the prediction of RAI therapy response and further contributes to the establishment of a proper therapy strategy for metastatic DTC in the early period.