Anesthetic management of anterior mediastinal masses (AMM) is challenging. We describe the successful anesthetic management of two patients with AMM in which dexmedetomidine was used at supra-sedative doses. Our first case was a 41-year-old man who presented with a 10 x 9 x 11 cm AMM, a pericardial effusion, compression of the right atrium, and superior vena cava syndrome. He had severe obstruction of the right mainstem bronchus, distal trachea with tumor compression, and endobronchial tumor invasion. Our second case was a 62-year-old man with tracheal and bronchial obstruction secondary to a recurrent non-small-cell lung cancer mediastinal mass. Both patients were scheduled for laser tumor debulking and treatment of the tracheal compression with a Y-stent placed through a rigid bronchoscope. Both patients were fiberoptically intubated awake under sedation using a dexmedetomidine infusion, followed by general anesthesia (mainly using higher doses of dexmedetomidine), thus maintaining spontaneous ventilation and avoiding muscle relaxation during a very stimulating procedure. The amnestic and analgesic properties of dexmedetomidine were particularly helpful. Maintaining spontaneous ventilation with dexmedetomidine as almost the sole anesthetic could be very advantageous and may reduce the risk of complete airway obstruction in the anesthetic management of AMMs.