Minimally invasive radio-guided surgery (MIRS) of parathyroid adenomas has been favoured by three main factors. One is the significant improvements achieved in preoperative localizing imaging, particularly with sestamibi scintigraphy. Another is the availability of intra-operative quick parathyroid hormone measurement, and finally the increase in availability of the intra-operative gamma probes in many surgical centres especially those performing sentinel node biopsy. In contrast with the traditional wide bilateral neck exploration (BNE), MIRS requires strict inclusion criteria: 1) high probability of a solitary parathyroid adenoma, 2) a significant sestamibi uptake in the parathyroid adenoma, 3) absence of a concomitant thyroid nodular disease, 4) no family history of familial hyperparathyroidism (HPT) of multiple endocrine neoplasia, 5) no previous neck irradiation. Following these criteria about 60-70% of all primary HPT patients are suitable for a MIRS. Two main protocols for MIRS have been proposed. The single day, imaging and surgery, protocol is based on the injection of a 740 MBq dose of 99mTc sestamibi with the purpose of obtaining scintigraphic imaging and then MIRS within 3 hours from radio-tracer injection. An alternative is for imaging to be performed a few days before surgery, with a further small administered activity of 37MBq of 99mTc sestamibi injected intravenously in the operating theatre a few minutes before commencing the intervention for the purpose of MIRS only. The latter protocol allows both better planning of operating theatre scheduling and reduction of the radiation exposure to the surgical staff. The main advantages of MIRS in respect to the traditional BNE include less surgical trauma, a shorter duration of anaesthesia and surgery, a shorter hospital stay with the possibility of same-day discharge, less post-surgical pain with improved cosmetic results and lower costs. Moreover, MIRS has proven to be a safe technique with a low morbidity rate and a cure rate higher than 95% in patients with primary HPT.