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Background: Primary hyperparathyroidism affects 1 in 700 individuals in the United States. A single adenoma is responsible in over 85% of cases. Surgery remains the most effective treatment. This study was designed to assess the feasibility of minimally invasive radioguided parathyroidectomy (MIRP) with confirmation of excision by ex vivo radioactivity alone., Methods: Seventy-five consecutive patients with primary hyperparathyroidism were prospectively studied. Following sestamibi scan, patients underwent unilateral neck exploration guided by a handheld gamma probe, which was also used to measure ex vivo radioactivity of excised tissue., Results: The sestamibi scan was positive in 88% of the patients. A small incision (mean, 3.2+/-0.3 cm) was sufficient. Ectopic gland sites were localized in five patients with positive scans and single adenomas. Mean operative time was 48 minutes (range, 15-125 minutes), with shorter procedures after the initial 20 cases (mean, 24 vs. 72 minutes; P < .01). Radioguided parathyroidectomy was successful in 97%, with a mean follow-up of 11 months (range, 1-26 months). As noted previously, adenomatous parathyroid glands contained more than 20% of the background radioactivity., Conclusions: MIRP is a feasible alternative to bilateral dissection with the advantages of guided dissection and rapid confirmation, and may become the procedure of choice for primary hyperparathyroidism.