Treatment with thyroid hormone is needed in patients with differentiated thyroid carcinoma (DTC) after the initial treatment (thyroidectomy followed, in most cases, by radioiodine remnant ablation) for two reasons: a) Correction of hypothyroidism in an athyreotic patient (replacement therapy); b) Blockade of thyrotropin (TSH) secretion in view of the TSH-dependence of DTC (TSH-suppressive therapy). Levothyroxine (L-T4) is the hormone of choice, since combination with levotriiodothyronine does not add any clear advantage with respect to L-T4 monotherapy. While replacement therapy obviously is a lifelong requirement, duration of TSH-suppressive therapy depends on the tumor risk stratification after and the response to the initial treatment. According to recent European and American guidelines, in low-risk DTC LT4 treatment should be carried out at TSH-suppressive doses until there is evidence that the patient is disease-free. In high-risk DTC, TSH suppression should be maintained for several years after such an evidence has been achieved. Afterwards, the patient can be shifted to replacement doses, also to avoid the risks of iatrogenic thyrotoxicosis, especially in the elderly and/or in the presence of cardiovascular disease. The dose of L-T4 must be invidualized; particular attention must be given to the coexistence of pathophysiological conditions or drug treatments that may affect L-T4 absorption or metabolism.