Thyroid disorders are common in patients with Down syndrome (DS). In these patients, hyperthyroidism occurs much less frequently than hypothyroidism, but it is likely to be underestimated. We report a case of an adult man with DS and hyperthyroidism. Ater 2 years of antithyroid therapy in a special facility, he was referred to our center with recurrence of hyperthyroidism with leukopenia and elevations of liver enzymes 14 months after remission. The patient underwent subtotal thyroidectomy, with rapid preparation with inorganic iodine and prednisone. After thyroidectomy the patient was found to have hypothyroidism and was given thyroid replacement therapy. We also review the literature on the treatment options for hyperthyroidism with DS. We conclude that the role of surgery in the treatment of hyperthyroid patients with DS has yet to be defined.