The radiolabeled glucose surrogate F-18-fluoro-deoxyglucose (F-18-FDG) and positron emission tomography (PET) were used to measure glucose metabolism of the thyroid in vivo. We evaluated patients with Graves' disease before therapy with radioiodine in comparison to patients with normal thyroids. Thirty-six patients with Graves' disease underwent scanning the day before radioiodine therapy. Twenty patients with head tumors and normal thyroids were the controls. Overall F-18-FDG uptake was determined for all thyroids and modeling of glucose metabolism was performed in order to differentiate between glucose concentration in the fractional blood volume, glucose transport, and glucose utilization. F-18-FDG uptake was significantly higher in Graves' disease patients compared with controls. In these patients F-18-FDG uptake increased with increasing antithyroid antibodies and shorter radioiodine half-life. Modeling of glucose metabolism revealed substantial differences in thyroid F-18-FDG utilization constants (k3 values) corresponding to enhanced local metabolic rates in Graves' disease. No significant differences in the remaining rate constants and the fractional blood volume were detected. These results indicate that glucose metabolism is enhanced in the thyroid of Graves' disease patients not only due to enhanced fractional blood volume but to enhanced utilization. Whether a lymphocytic infiltration or thyroid epithelial cells utilize this surplus of glucose cannot be determined using in vivo PET measurements in humans. Still, the correlation of radioiodine half-life and glucose hypermetabolism suggests direct or nondirect connections of glucose metabolism and hormone synthesis in thyroid cells.