To evaluate the role of PET-CT with FDG-18F in the detection of recurrence and/or metastasis of differentiated thyroid carcinoma (DTC) in patients with elevated levels of thyroglobulin (TG) and negative whole body scan (WBS). PET-CT findings of 25 patients were compared to histopathology evaluation and conventional imaging (CI). PET-CT scan was positive in 16 patients finding 14 true-positive and 2 false-positive cases (positive predictive value 87.5%). Nine patients had negative PET-CT; two had decrease of TG to undetectable levels. One patient had residual disease detected by post-therapeutic WBS. Six patients had no evidence of tumor during follow-up (mean time 16 months). PET-CT was concordant with CI in 52%, partially concordant in 12% and discordant in 36% (6 false-negatives and 3 false-positive of CI). We observed a tendency of increasing proportion of positive PET-CT with increasing TG. PET-CT scan with FDG-18F is useful in the detection of recurrence and/or metastases of DTC with high TG levels but negative WBS. It presents elevated positive predictive value and is superior to CI being more effective as higher the serum TG levels.