Background: The aim of this paper is to state the role of radio-guided surgery (RGS) in case of recurrent secondary hyperparathyroidism. Methods: Two cases of recurrent secondary hyperparathyroidism were treated using RGS. After a preoperative assessment, which included ultrasonography (US), MRI and <sup>99m</sup>Tc-radiolabelled sestamibi scan, a radio-guided neck re-exploration was planned. On the day of surgery the patients underwent a radionuclide injection. After 90 min, surgery began. Results: Dissection was guided by placing the probe in the wound to localize any increased concentration of radioactivity. In the first case the probe identified the gland located deeply in the right tracheo-esophageal groove; in the other case the probe detected a site of increased uptake in the upper mediastinum. Both lesions were dissected and excised; a frozen section confirmed they were parathyroid glands with diffuse hyperplasia. The operative time was less than 60 min in both cases. The patients were discharged on the first postoperative day. A decrease in serum calcium and PTH was observed subsequently. A minimum follow-up of 6 months did not show any recurrence. Conclusion: RGS can help in detecting the parathyroid tissue in selected cases of renal hyperparathyroidism and makes operation much easier and more predictable.