Thioredoxin (TRX), which is a stress-inducible protein with redox-active disulfide structures, has various biological activities by regulating DNA binding of transcription factors in cells. In Graves' disease that is among the common diseases of the thyroid, endogenous stresses that are induced by excess thyroid hormones or antibodies against thyroid stimulating hormone (TSH) receptors are responsible for the pathogenesis. The objective of this study was to examine the expression of TRX and to determine whether TRX is responsible for the pathogenesis of Graves' disease. The thyroid follicular cells were shown to express both TRX and vascular cell growth factors (VEGF) in all of the patients with Graves' disease by immunohistochemistry. In contrast, the expression of TRX or VEGF was not found in any of the normal thyroids. Serum levels of TRX were significantly elevated in patients with Graves' disease regardless of their thyroid function compared to those in healthy donors (122+/-16 versus 37+/-5 ng/ml, p<0.0001). Consecutive administration of iodine resulted in not only a reduction in serum levels of free triiodothyronine (T3) but also an increase in serum levels of TRX in the patients. These findings suggest that release of intracellular TRX from thyroid follicular cells in response to iodine resulted in suppression of T3 production. Taken together, TRX is highly produced under stress in Graves' disease and involved in regulating production of thyroid hormones. The investigation of biological behavior of this molecule may greatly help to understand pathogenesis of Graves' disease functions.