The objective of this prospective study was to evaluate the role of preoperative ultrasonography (US) for parathyroid lesion localization in patients with primary hyperparathyroidism (PHPT) prior to initial surgery. Fifty-two consecutive patients with PHPT, diagnosed in our institution within a period of 2 years, were referred for preoperative US and subsequently for bilateral surgical neck exploration. The combination of a confirmatory pathologic report and normalization of blood calcium concentration for a period of at least 3 months was considered an operative success. In 50 patients (96.2%) a single parathyroid adenoma was excised, and in one patient (1.9%) hyperplasia of three glands was found at surgery. In the one surgical failure, no parathyroid pathology was identified in the neck; therefore the operative success in this series was 98%. The sensitivity of preoperative US was 83% with a specificity of 100%. In the absence of thyroid multinodular disease (MND), the sensitivity of preoperative US increased to 90%, whereas in patients with MND the sensitivity was only 64%. Our findings support the notion that patients with PHPT should be investigated with US before initial surgery. Bilateral surgical exploration is warranted in patients with MND. In the absence of such thyroid pathology, an US finding positive for adenoma should allow the surgeon to perform unilateral neck exploration only, with consequent reduction of operation time and postoperative complications.