Despite the excellent results with bilateral exploration, minimally invasive parathyroidectomy has become the procedure of choice for patients with hyperparathyroidism in which a single parathyroid lesion can be localized preoperatively. In this article, we discuss a patient who presented with primary hyperparathyroidism for the first time and had a Tc-99m sestamibi scan to localize a single parathyroid lesion in the left, anterior mid-mediastinum. We subsequently performed a radioguided parathyroidectomy via video-assisted thoracoscopic surgery (VATS) to resect this parathyroid adenoma and used intraoperative parathyroid hormone (PTH) testing to confirm cure and avoid neck exploration. We concluded that radioguided parathyroidectomy via VATS combined with intraoperative PTH testing is an effective approach for patients with primary hyperparathyroidism and mediastinal parathyroid lesions, and perhaps should be the technique of choice.