BACKGROUND Recent publications have recommended parathyroidectomy guided solely by preoperative imaging. However, when the parathyroid adenoma is located deep in the mediastinum, the surgeon often encounters difficulties to localize and completely remove all hyperfunctioning parathyroid tissues. Thus, we hypothesized that patients with mediastinal adenoma differ substantially from cervical cases and require a specific strategy. The aim of this study was to evaluate the efficacy of intraoperative serum parathyroid hormone monitoring (ioPTH) used to guide completeness of targeted mediastinal parathyroidectomy. METHODS In a 10-year period, 33 patients underwent targeted mediastinal parathyroidectomy with ioPTH for primary sporadic hyperparathyroidism. A greater than 50% drop in ioPTH was considered confirming successful resection. If ioPTH failed to decline adequately, the operation was extended to complete cervical exploration. We analyzed the impact of ioPTH on the final surgical outcome. RESULTS In 26 patients the adenoma was correctly identified and removed at targeted mediastinal parathyroidectomy. In 7 patients lack of adequate ioPTH drop after targeted mediastinal parathyroidectomy triggered continued exploration, providing success at complete cervical exploration in 6 patients. In 1 patient this strategy failed owing to an undiagnosed lesion in the posterior mediastinum. Use of ioPTH decreased the failure rate from a potential 21.2% without ioPTH to 3% in the actual series. CONCLUSIONS Mediastinal parathyroid adenoma represents a distinct subset of primary hyperparathyroidism and requires a specific diagnostic and therapeutic approach. In these cases ioPTH monitoring is a reliable and effective method to confirm curative resection. It is an important adjunct predictor of postoperative successful outcome, which allows a low failure rate and avoids unnecessary reoperations.