Patients with substernal thyroid disease, defined by the presence of enlarged thyroid tissue below the plane of the thoracic inlet, were identified from a prospective database maintained for patients who have undergone thyroidectomy at our institution since 1990. Substernal thyroid disease was present in 116 (30%) of 381 patients, anterior mediastinal in 109 (94%), and posterior mediastinal in seven (6%). Indications for surgery included compressive symptoms in 75 (65%) patients, an abnormal fine-needle biopsy in 45 (39%), progressive thyroid enlargement in 41 (35%), thyrotoxicosis in 11 (10%), and superior vena cava syndrome in two (1.7%). A median sternotomy and thoracotomy were performed in one patient each for a primary intrathoracic goiter. In all other patients thyroidectomy was accomplished through a cervical incision. Parathyroid autotransplantation was performed in 41 (37%) patients with retrosternal disease compared with 57 (22%) with disease confined to the neck (P < 0.01). Twenty-five patients (22%) had malignancy; four of these had unresectable disease. Postoperative complications included transient hypocalcemia (n = 46), transient hoarseness (n = 7), recurrent laryngeal nerve injury (n = 1), and wound infection (n = 1). One patient died from aspiration pneumonia. In summary, substernal thyroid disease is typically present in the anterior mediastinum and with rare exceptions can be resected through a cervical incision. Parathyroid devascularization is more common with resection of a substernal goiter and autotransplantation can prevent permanent hypoparathyroidism.