Background: The majority of ectopic mediastinal parathyroid adenomas are accessible transcervically and those not amenable to this approach pose a significant clinical and technical challenge. Methods: Retrospective review of transthoracic robot-assisted mediastinal parathyroidectomy (TTRMP) for primary hyperparathyroidism between 2012 and 2019 at a single institution. Results: 16 patients underwent TTRMP, 63% were female with a mean age of 64 ± 2.0 years. Nine of 16 had prior parathyroidectomy; 80% had persistent disease and a mean 2.8-year delay from index operation until TTRMP. Locations included: intrathymic (8), AP window (4), carina (3), and retroesophageal (1). Two patients underwent parathyroid reimplantation. Mean post-operative calcium and PTH were 9.2 ± 0.2 mg/dL and 20.2 ± 5.6 pg/mL, respectively. Complications included: temporary hypocalcemia (4), permanent hypocalcemia (1), DVT (1), hoarseness (1), and subcostal neuralgia (1). Conclusion: In experienced hands, TTRMP is a safe and effective approach to mediastinal parathyroids not accessible transcervically. A multidisciplinary approach should be used in reoperative cases.