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This study was designed to determine if a rising intraoperative parathyroid hormone (ioPTH) level following parathyroid resection indicates multiple hyperfunctioning glands and to determine the appropriate intraoperative management.IoPTH monitoring is commonly used to guide parathyroid surgery. A significant rise in the ioPTH immediately after resection of a single parathyroid is often perceived to be indicative of the presence of additional hyperfunctioning glands.A total of 797 consecutive patients underwent parathyroidectomy for primary hyperparathyroidism with ioPTH monitoring. Patients with an elevated 5 minute ioPTH were extensively studied. Operative success was defined as normocalcemia 6 months after surgery.Of the 797 patients, 108 (14%) had a rising ioPTH 5 minutes after resection of a single parathyroid. Of these 108 patients, 36 (33%) continued to have elevated ioPTH levels and further exploration revealed additional hyperfunctioning glands. Importantly, in the majority of patients (n = 72 or 67%), the ioPTH started to fall after an additional 5 minutes (10 minutes after resection). The ioPTH declined by more than 50% from the 5 minute elevated value in 30%, 89%, and 99% of patients at 10, 15, and 20 minutes after resection, respectively. Importantly, this fall correctly predicted operative success in 100% of patients after removal of a single abnormal gland.A rising ioPTH level immediately after parathyroidectomy is observed in 14% of patients. The majority of these patients do not have additional hyperfunctioning glands. Most of patients fell below 50% of the 5 minute elevated value within 20 minutes of gland resection and in all cases this fall correctly predicted operative success.