Objectives/Hypothesis: Critical evaluation of a directed exploration protocol used by a single surgeon in the management of surgical parathyroid disease. Study Design: Retrospective chart review was made of patients surgically managed for hyperparathyroidism at an academic tertiary care center. Methods: Three hundred forty-six patients were evaluated for biochemically proven hyperparathyroidism between March 1995 and February 2002. A directed exploration protocol was implemented in appropriately selected patients with primary hyperparathyroidism and in patients with secondary or tertiary hyperparathyroidism requiring repeat operation. The protocol included preoperative technetium-99m sestamibi imaging for hyperfunctional parathyroid localization, targeted neck exploration, rapid intraoperative parathyroid hormone determination, and limited-stay discharge from the ambulatory surgical recovery unit. Data collection was accomplished by entering patient evaluation, management, and outcome information prospectively into collective case report forms. A retrospective analysis of the data was conducted for the purpose of evaluating the effectiveness of the protocol. Results: Sustained normocalcemia beyond 6 months postoperatively was achieved in 323 of 327 (99%) patients with primary hyperparathyroidism. Eighty-four percent (84%) of patients with secondary or tertiary hyperparathyroidism achieved normocalcemia or had resolution of symptoms as a measure of therapeutic success. The complication rate for the entire series of patients was 2.8%. Ninety-two percent of positive findings on sestamibi scan correctly predicted the location of an adenoma, whereas a negative finding accurately predicted the absence of an enlarged gland in a “usual” location in 81% of patients. Twenty-six patients (9%) had a false-positive finding on the scan, whereby a solitary adenoma was found contralateral to the side indicated by the scan. Overall, the positive predictive value for sestamibi imaging in the series was 91%. Intraoperative parathyroid hormone determination yielded an overall rate of reduction of 80% from preoperative levels during directed exploration. Sustained normocalcemia was achieved in all patients in whom intraoperative parathyroid hormone determination demonstrated a minimum decline of 50% from preoperative levels following resection of hyperfunctional parathyroid tissue (adenoma[s]). The majority (72%) of patients were managed in an outpatient (ambulatory surgery) setting and were discharged to home within 8 to 12 hours after surgery. Conclusion: The directed exploration protocol for surgical management of hyperparathyroidism generated surgical rates of success that were as good as and, in most cases, improved over that of traditional bilateral exploration. This achievement was associated with low morbidity and reduced time and facility utilization, conveying improved cost-effectiveness. This surgical strategy should serve to enhance the capability of the surgeon to safely and efficiently manage the majority of patients with surgical parathyroid disease.