Objective: While intraoperative parathyroid hormone (IOPTH) monitoring with a ≥50% drop commonly guides the extent of exploration for primary hyperparathyroidism (pHPT), receiver operating characteristic (ROC) analysis has not been performed to determine whether other criteria yield better sensitivity and specificity. The aim of this study was to identify the optimum percent change of IOPTH following removal of the abnormal parathyroid pathology, in order to predict biochemical cure. Secondary aims were to identify patient subgroups with increased area under the ROC curve (AUC) and the need for moderated criteria. Methods: A retrospective review was performed on patients undergoing primary parathyroid surgery for sporadic pHPT between 1999 and 2010 at a tertiary center for endocrine surgery. Eight hundred and ninety-six patients with primary hyperparathyroidism were included. Multigland disease (MGD) was defined as the intraoperative detection of more than 1 enlarged hypercellular gland or persistent disease after single gland excision. ROC analysis was used to determine the value with the best performance at predicting MGD, following bilateral exploration. Results: MGD was diagnosed in 174 patients (19.4%). ROC analysis demonstrated an AUC of 0.69. An IOPTH drop of 72% was the point of optimal discrimination with a sensitivity of 55% and specificity of 76% for predicting MGD. Subgroup analysis by preoperative calcium, preoperative PTH, localization studies, or pre- and post-excision IOPTH, did not identify any factors associated with an improved AUC. Conclusion: To our knowledge, this is the first study to use ROC analysis in a large patient cohort. An IOPTH drop of 72% was found to have optimal discriminating ability. We failed to identify a subset of patients for whom there was substantial improvement in the AUC, sensitivity, or specificity. Abbreviations: AUC = area under the ROC curve; BE = bilateral neck exploration; FE = focal parathyroid exploration; IOPTH = intraoperative parathyroid hormone; MGD = multigland disease; MIBI = Tc99m-sestamibi I-123 subtraction single-photon emission computed tomography/computed tomography; pHPT = primary hyperparathyroidism; ROC = receiver operating characteristic; SGD = single gland disease; US = surgeon-performed neck ultrasound.