In a previous paper, we demonstrated that the acute administration of excess iodide inhibits the adenylate cyclase-cAMP system in mouse thyroid lobes. In the present study, we examined whether presurgical therapy with stable iodide reduces the responsiveness to TSH in thyroid tissues from patients with Graves' disease. Eight patients with Graves' disease were presurgically treated with methimazole and stable iodide and six were given methimazole alone. Normal tissues from five patients with thyroid nodules were also tested. We have found that stimulation by TSH (5 and 50 mU/ml) of cAMP formation in thyroid slices from patients preoperatively treated with methimazole and iodide is significantly less than in slices from patients treated with methimazole alone. Similar observations were also made with other thyroid stimulators, such as prostaglandin E2 and 4-methylhistamine. Furthermore, thyroid slices from patients treated with methimazole alone responded to TSH to the same degree as slices of normal tissues. The data suggest that one of the reasons for the hyporesponsiveness to TSH in thyroids from patients with Graves' disease is preoperative treatment with stable iodide.