The main purposes of this study were: (a) to investigate the efficacy of an imaging protocol based on the combination of 99mTcO4/MIBI scintigraphy and neck ultrasound (US) in selecting patients with primary hyperparathyroidism (HPT) for unilateral neck exploration, and (b) to help define the role of the intraoperative MIBI gamma probe (IMGP) technique in the performance of minimally invasive radio-guided surgery (MIRS). One hundred and forty-three consecutive patients with primary HPT were enrolled in the study. We used a modified 99mTcO4/MIBI scintigraphic procedure which included the oral administration of potassium perchlorate to cause rapid 99mTcO4 washout from the thyroid tissue, thereby permitting the acquisition of high-quality early MIBI images. A single-photon emission tomography (SPET) acquisition was also obtained in 21 patients, of whom seven had an enlarged parathyroid gland (EPG) in the mediastinum at planar scintigraphy and 14 had discordant scan/US findings for the presence of a cervical EPG. Neck US was performed in the same session as scintigraphy using a small-parts, high-resolution 10-MHz transducer. All patients were then operated on by the same surgical team. Quick PTH assay (QPTH) was used to measure PTH intraoperatively to confirm successful parathyroidectomy. In patients with scan/US evidence of a solitary EPG and with a normal thyroid gland, limited, unilateral neck surgery or, more recently, MIRS was planned (n=91). In patients with scan/US evidence of multiglandular disease (MGD) (n=21) or concomitant nodular goitre (n=24) or in patients with a negative scan/US evaluation (n=7), extensive bilateral neck exploration was planned (n=52). In 87 of the 91 patients (95.6%) in whom preoperative imaging indicated the presence of a solitary EPG and a normal thyroid gland, a single parathyroid adenoma was found at surgery, and these patients were treated by unilateral neck exploration or MIRS. In the remaining four patients of this group, conversion to bilateral neck exploration was required because parathyroid carcinoma (n=3) or MGD (n=1) was diagnosed at operation. In some cases SPET was helpful in better localising the EPG. In particular, in 5 of the 21 patients evaluated, SPET localised an EPG deep in the neck or mediastinum and at surgery a parathyroid adenoma was found in the paratracheal or para-oesophageal space. In 43 of the 46 patients (93.5%) who were candidates for MIRS, the IMGP technique allowed parathyroidectomy to be performed through a small, 2- to 2.5-cm skin incision with a short duration of intervention (mean 34 min). We conclude that: (a) The integrated scan/US imaging protocol that we used appears to be accurate in selecting patients with primary HPT for unilateral neck exploration. (b) In our series the most prevalent cause of bilateral neck exploration was the co-existence of a nodular goitre; thus accurate preoperative evaluation of the thyroid gland by dual-tracer scintigraphy and US imaging is strongly recommended in all patients with HPT. (c) SPET can provide the surgeon with useful information when an EPG is located deep in the neck or mediastinum. (d) IMGP appears to be a useful intraoperative device in HPT patients with solitary parathyroid adenomas and a normal thyroid gland, since it permits minimally invasive and time-saving surgery.