Objective: 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. Summary background data: 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. Methods: 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. Results: 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. Conclusions: 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. © 2010 Lippincott Williams & Wilkins.