In the follow-up of differentiated thyroid carcinoma (DTC), after total thyroidectomy and Iodine-131 therapy, thyroglobulin (Tg) levels and Iodine-131 total body have particular importance. The Tg level becomes a specific and very sensitive marker of DTC recurrence: it is usually evaluated after eradication of thyroid residual tissue (by thyroidectomy and radiometabolic therapy), in presence of high level of TSH (>35 microU/ml) obtained with the suspension of therapy or after rec-TSH administration and in absence of anti-Tg antibodies. Usually, to solve diagnostic problems in patients with negative total body Iodine-131 and high levels of thyroglobulin, we consider one or more of the following investigations, on the basis of prognostic factors: radiological examinations (neck US, skeletal X-ray, CT chest and abdomen, MRI) and scintigraphy (bone scintigraphy, Tc-MIBI or Tl-201 scintigraphy, octreoscan, PET/CT). The use of PET is well known in patients in whom carcinoma metastases are strongly suspected and who are unable of concentrating Iodine-131. In order to increase the PET sensitivity, scintigraphy is performed with high TSH levels obtained through a rec-TSH injection on the 1st and 2nd day, PET/CT scan and blood withdrawal (for Tg level evaluation) on the 3rd day. Considering the hypothesis of a recurrence with lesion size below the resolution power of the diagnostic equipment (5 mm), if PET/CT results are negative, the patients are strictly followed-up and Tg is monitored every 4-6 months. An alternative hypothesis might be not to consider the negative-PET patients as sick persons, but to attribute high Tg levels to illegitimate transcription of mRNA for Tg by the non-thyroid cells or to ectopic thyroid tissue (e.g. intrathymus). Positive PET/CT patients are evaluated for a possible surgical removal of the lesions or alternative appropriate therapies.