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There are no standardized prognostication algorithms for metastatic radioiodine-refractory (RAI-R) differentiated thyroid cancer (DTC). We hypothesize that [18F]-FDG PET/CT may predict progression versus stability of disease based on quantitative analysis of metabolic tumor volume (MTV) and total lesion glycolysis (TLG).Retrospective study of 62 patients with metastatic RAI-R DTC to determine clinical outcomes with median follow-up from initial diagnosis of 11.1 years (8.38, 14.1) (range, 1.2–20 years). Baseline [18F]-FDG PET/CT scans were evaluated qualitatively for regional and distant metastases and quantitatively for tumor burden based on MTV and TLG obtained using gradient segmentation method.After diagnosis of metastatic RAI-R disease was established, the 5-year overall survival (OS) probability was 34%, and median OS was 3.56 years (2.87, infinity). The 5-year progression-free survival (PFS) probability was 19%, and median PFS was 1.31 years (1.03, 2.38). TSH-suppressed thyroglobulin (Tg) levels greater than 100 ng/mL and Tg doubling time (Tg-DT) less than 6 months were significantly associated with worse OS and PFS. Higher than median values of MTV and TLG were associated with worse OS (P = 0.06) and PFS (P = 0.007). Higher hazard of death was noted for higher values of log-MTV and log-TLG (HR, 1.17 [95% confidence interval, 0.99–1.39], P = 0.05, and HR, 1.14 [95% confidence interval, 1.00–1.31], P = 0.05, respectively).[18F]-FDG PET/CT metabolic parameters can help define the volume and biologic variations of metastatic tumor burden. Metabolic tumor volume and TLG can be used for dynamic risk stratification of patients with metastatic RAI-R DTC regarding PFS and complement Tg-DT for prognosis of clinical disease course.