Antithyroid treatment effectively restores euthyroidism in patients with Graves' hyperthyroidism. After a few months of treatment, patients are clinically euthyroid with normal levels of thyroid hormones, but in many patients TSH levels remain suppressed. We postulated that TSH receptor autoantibodies could directly suppress TSH secretion, independently from thyroid hormone levels, via binding to the pituitary TSH receptor. To test this hypothesis, we prospectively followed 45 patients with Graves' hyperthyroidism who were treated with antithyroid drugs. Three months after reaching euthyroidism, blood was drawn for the analysis of thyroid hormones, TSH, and TSH binding inhibitory Ig (TBII) levels. After 6.7 +/- 1.5 months since start of antithyroid treatment, 20 patients still had detectable TBII levels, and 25 had become TBII negative. The two groups had similar levels of free T(4) and T(3), but TBII-positive patients had lower TSH values than TBII-negative patients: median 0.09 (range < 0.01-4.30) mU/liter vs. 0.84 (0.01-4.20; P = 0.015). In addition, TSH levels correlated only with TBII titers (r = -0.424; P = 0.004), and not with free T(4) or T(3) values. Our findings suggest that TBII suppress TSH secretion independently of thyroid hormone levels, most likely by binding to the pituitary TSH receptor.