We report a large series of 25 patients with TSH-secreting tumors (23 macroadenomas) followed at the NIH. Hyperthyroid symptoms were severe in 14 patients, mild in 8, and absent in 3. Patients were divided into 2 groups according to whether their thyroid had been treated (n = 11) or not (n = 14). In untreated patients, the classical diagnostic criteria (unresponsive TRH test, high alpha-subunit, and high alpha-subunit/TSH ratio) were present, respectively, in 10, 8, and 12 cases (sensitivity, 71%, 75%, and 83%; specificity, 96%, 90%, and 65%). In treated patients, the respective sensitivities of the TRH test, alpha-subunit, and alpha-subunit/TSH ratio were 64%, 90%, and 90%, and their specificities were 100%, 82%, and 73%. Studies of thyroid hormone action revealed no evidence of acquired resistance to thyroid hormone in TSH-secreting tumors. Apparent cure was achieved in 35% of cases by surgery alone and in 22% more by combined therapies. Three deaths occurred, including 1 from metastatic thyrotroph carcinoma. Six patients had residual tumor, with symptoms of hyperthyroidism controlled with octreotide in 5. The size and invasiveness of the tumor, duration of symptoms, and intensity of hyperthyroidism were the main prognostic factors. Thus, early diagnosis and treatment are the keys to a good outcome.