We performed this study to compare a sestamibi-only radio-guided approach (MIBI) versus using intraoperative parathyroid hormone monitoring (IOPTH) in the performance of minimally invasive parathyroidectomy (MIP) in patients with a clearly positive preoperative sestamibi scan from January 2000 to June 2010. Five of 81 patients in the MIBI group required additional surgery, three at the time of MIP when the intraoperative findings were in conflict with the preoperative sestamibi scan and two required a second operation as a result of an undiscovered second adenoma. In the IOPTH group, five patients had an unnecessary bilateral neck exploration as a result of an inadequate drop in PTH levels, whereas six had their disease cured because the PTH levels predicted additional pathology. One patient in the IOPTH group remains hypercalcemic and represents the only surgical failure in this study. The MIBI group had a shortened operating room time and less cost (P < 0.001). No deaths or complications, including recurrent laryngeal nerve injuries, occurred in this study. Although both strategies are effective in managing hyperparathyroidism, a MIBI-only approach is less expensive and has shorter operative times with an occasional need for reoperation, whereas the IOPTH group results in more extensive surgery that will occasionally be unnecessary.