The novel trend toward focused parathyroidectomy requires precise preoperative localization of the parathyroid adenoma in patients with primary hyperparathyroidism (PHPT). The present study evaluated the impact of hybrid single photon emission computed tomography/computed tomography (SPECT/CT), using 99mTc-sestamibi (MIBI), on the surgical management of these patients. In a retrospective study of 36 patients with PHPT, SPECT/CT was undertaken when planar 99mTc-MIBI scintigraphy was negative or when an ill-defined focus in the neck or an ectopic site on planar views was visualized. Imaging data were compared with intraoperative findings, and the incremental value of SPECT/CT to lesion localization and surgical procedure was assessed. Three patients with both negative planar and SPECT/CT studies subsequently underwent bilateral neck exploration, with multiglandular hyperplasia diagnosed in two patients and a parathyroid adenoma in one. Of 33 patients with a positive MIBI study, parathyroid adenoma was confined to the neck in 23 patients and to the lower neck-mediastinum in 10. SPECT/CT facilitated the surgical exploration of all 10 ectopic parathyroid adenomas and 4 of 23 cervical parathyroid adenomas, the latter four either at reexploration or in patients with nonvisualization of the thyroid after thyroidectomy. SPECT/CT contributed to the localization of parathyroid adenomas in patients with PHPT and to planning the surgical exploration in 14 of 36 (39%) patients, predominantly those with ectopic parathyroid adenomas or who had distorted neck anatomy.