The clinical and prognostic role of 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/computed tomography (2-[18F]FDG PET/CT) in the study of patients affected by differentiated thyroid carcinoma (DTC) with positive serum thyroglobulin (Tg) level and negative [131I] whole-body scan ([131I]WBS) has already been demonstrated. However, the potential prognostic role of semi-quantitative PET metabolic volume features, such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG), has not yet been clearly investigated. The aim of this retrospective study was to investigate whether the main metabolic PET/CT parameters may predict the prognosis. We retrospectively included 122 patients with a positive 2-[18F]FDG PET/CT for DTC disease after a negative [131I]WBS with Tg > 10 ng/mL. The maximum and mean standardized uptake value (SUVmax and SUVmean), MTV and TLG of the hypermetabolic lesion, total MTV (tMTV) and total TLG (tTLG) were measured for each scan. Progression-free survival (PFS) and overall survival (OS) curves were plotted according to the Kaplan–Meier analysis. After a median follow up of 53 months, relapse/progression of disease occurred in 87 patients and death in 42. The median PFS and OS were 19 months (range 1–132 months) and 46 months (range 1–145 months). tMTV and tTLG were the only independent prognostic factors for OS. No variables were significantly correlated with PFS. The best thresholds derived in our sample were 6.6 cm3 for MTV and 119.4 for TLG. In patients with negative WBS and Tg > 10 ng/mL, 2-[18F]FDG PET/CT metabolic volume parameters (tMTV and tTLG) may help to predict OS.