BACKGROUND Scintigraphy of the hyperfunctioning parathyroid glands using technetium 99m ((99m)Tc)-methoxyisobutylisonitrile ((99m)Tc-MIBI) is an established and highly sensitive preoperative localization tool whose importance has been further increased by advances in minimally invasive surgery . The goal of the present prospective study was to determine the benefit of optimized imaging in a consistent patient population. METHODS Eighty-four patients with first presentations of primary hyperparathyroidism were investigated with (99m)Tc-MIBI scintigraphy, thyroid scintigraphy, and cervical ultrasonography. The evaluation algorithm consisted of (a) evaluation of the planar images alone, (b) additional evaluation of single-photon emission computed tomography (SPECT), (c) additional evaluation of thyroid gland scintigraphy, and (d) additional evaluation of ultrasound. All patients subsequently underwent parathyroidectomy. The intraoperative and the histologic findings were correlated with the results of the scintigraphic imaging. RESULTS The sensitivity of planar parathyroid scintigraphy was 74% and could be increased to 91% by the additional investigations. The difference was statistically significant (p<0.05). At the same time, a small increase in specificity from 96% to 99% was seen. CONCLUSIONS Prior to minimally invasive treatment of hyperparathyroidism, we recommend combined localization studies consisting of sequential (99m)Tc-MIBI scintigraphy, additional SPECT plus thyroid gland scintigraphy, plus high-resolution cervical ultrasonography.