Objectives: Develop a protocol for the localization of parathyroid adenoma and characterization of nodular thyroid lesions in order to optimize the application of a minimally invasive approach to hyperparathyroidism. Methods: A retrospective evaluation of 466 patients with primary hyperparathyroidism in whom directed exploration was performed by a single surgeon at an academic tertiary care medical center. The study population consisted of patients for whom surgical findings indicated a false-positive preoperative technetium 99m sestamibi scan. Results: The accuracy of sestamibi imaging in predicting the location of parathyroid adenoma was 92%. Thirty-two patients were found to have surgical findings inconsistent with the location predicted by the scan (false-positive scans). The presence of concurrent thyroid abnormalities was noted in all 32 patients, the location of the abnormality coinciding with the area of delayed uptake noted on the scan. In total, 60 patients demonstrated obvious thyroid abnormalities at exploration. All thyroid lesions demonstrating retained radiotracer were solid whereas the remaining 28 nodules were cystic and did not concentrate sestamibi. Twenty-three of the 32 patients with false-positive imaging demonstrated clinically palpable thyroid nodules preoperatively. Conclusions: In the presence of a known or clinically demonstrated thyroid abnormality in patients with hyperparathyroidism and focal uptake of sestamibi, a high resolution ultrasound of the thyroid gland will be of benefit in assessing the risk for a false positive localization scan, ie, cystic vs solid nodule. This will determine the applicability of a directed minimally invasive approach.