OBJECTIVE: To compare unilateral and bilateral neck exploration for primary hyperparathyroidism in a prospective randomized controlled trial. SUMMARY BACKGROUND DATA: Based on the assumption that unilateral neck exploration for a solitary parathyroid adenoma should reduce operating time and morbidity, a variety of minimally invasive procedures have challenged the idea that bilateral neck exploration is the gold standard for the surgical treatment of primary hyperparathyroidism. However, to date, no open prospective randomized trial has been published comparing unilateral and bilateral neck exploration. METHODS: Ninety-one patients with the preoperative diagnosis of primary hyperparathyroidism were randomized to unilateral or bilateral neck exploration. Preoperative scintigraphy and intraoperative parathyroid hormone measurement guided the unilateral exploration. Gross morphology and frozen section determined the extent of parathyroid tissue resection in the bilateral group. The primary end-point was the use of postoperative medication for hypocalcemic symptoms. RESULTS: Eighty-eight patients (97%) were cured. Histology and cure rate did not differ between the two groups. Patients in the bilateral group consumed more oral calcium, had lower serum calcium values on postoperative days 1 to 4, and had a higher incidence of early severe symptomatic hypocalcemia compared with patients in the unilateral group. In addition, for patients undergoing surgery for a solitary parathyroid adenoma, unilateral exploration was associated with a shorter operative time. The cost for the two procedures did not differ. CONCLUSIONS: Patients undergoing a unilateral procedure had a lower incidence of biochemical and severe symptomatic hypocalcemia in the early postoperative period compared with patients undergoing bilateral exploration. Unilateral neck exploration with intraoperative parathyroid hormone assessment is a valid surgical strategy in patients with primary hyperparathyroidism with distinct advantages, especially for patients with solitary parathyroid adenoma