Responsiveness to synthetic thyrotropin-releasing hormone (TRH), thyroid suppressibility by triiodothyronine (T3) and the outcome of hyperthyroidism following prolonged therapy with thionamides were studied in a group of 35 patients with toxic diffuse goiter. TRH and T3 suppression tests were performed 10 days to 24 months (mean 4 months) after withdrawal of antithyroid drugs. Nineteen patients were euthyroid and had a normal thyrotropin (TSH) response to TRH, while 4 were recovering from mild hypothyroidism due to overtreatment and had an exaggerated response. No response was observed in 12 patients with recurrent hyperthyroidism. Positive T3 suppression tests were found only in 10 of the 30 cases examined. Peak and net 2 h secretion responses of TSH to TRH exhibited a significant inverse correlation with the levels of serum thyroxine and serum triiodothyronine, but were unrelated to the degree of thyroid suppressibility. Relapse or recurrence of thyrotoxicosis occurred in at least 9 of the 23 patients having no evidence of hyperthyroidism at the time of TRH test. Each of them was found to be responsive to TRH, while the T3 suppression test was negative in 8 and had to be discontinued in one because of thyrotoxic symptoms. The present data indicate that during the early period after completion of a prolonged course of antithyroid drug therapy responsiveness to TRH in toxic diffuse goiter is: a) correlated with circulating thyroid hormones, b) unrelated to the degree of thyroid suppressibility by T3 and c) of little value in predicting the long-term results of treatment.