The classical therapeutic approach to patients with differentiated thyroid cancer (DTC) is based on total or near-total thyroidectomy, followed by (131)I treatment and thyroid-stimulating hormone suppressive therapy. This approach allows complete cure in many patients, especially when the tumour is diagnosed at an early stage; it also allows long-term survival in patients with locoregional recurrences or distant metastases if they can be treated with (131)I. In contrast, when metastatic DTC deposits lose their ability to trap (131)I (non-functioning metastases), a worse prognosis is expected. Nevertheless, in patients with locoregional non-functioning recurrences, an early diagnosis and prompt surgical extirpation can lead to a favourable prognosis. In these cases, radical surgery is needed. This can be achieved with radio-guided surgery using a hand-held gamma probe and a tumour-seeking radiotracer to detect, intraoperatively, the smallest metastatic lesions. In this paper, we discuss the two principal techniques proposed in the literature for radio-guided surgery of non-functioning DTC metastatic recurrences, the first using high doses of (131)I and the second using low doses of 99mTc-Sestamibi.