OBJECTIVE To report an unusual case that illustrates the difficulties in distinguishing neoplastic (nIST) from nonneoplastic inappropriate secretion of thyrotropin (nnIST). METHODS We describe clinical, biochemical, genetic analysis, and magnetic resonance imaging (MRI) results in a patient with hyperthyroidism due to IST, and we review the related literature. RESULTS The patient demonstrated overt clinical and biochemical hyperthyroidism with inappropriately increased thyrotropin levels, which failed to respond to thyrotropin-releasing hormone (TRH) stimulation. Sex hormone-binding globulin (SHBG) levels were in the hyperthyroid range. Alpha subunit levels were normal, as was the alpha subunit/thyrotropin molar ratio. MRI of the pituitary was negative for tumor during a 2-year period, and octreotide scan was also negative for sellar uptake. Basal oxygen consumption was abnormally increased. Genetic analysis failed to reveal mutations of the thyroid receptor b gene. The patient responded well to radioiodine ablation of his thyroid. CONCLUSIONS This patient had clinical symptoms of hyperthyroidism associated with some features characteristic of nIST (increased level of SHBG, lack of thyrotropin response to TRH stimulation, absence of thyroid receptor b mutations) and others typical of nnIST (normal alpha subunit and its molar ratio to thyrotropin, absence of tumor on sellar imaging). Close follow-up with periodic MRI of the sella is important because of the possible existence of a small pituitary tumor, which may become apparent at a later date. Therapy to control symptoms is important. Hormone replacement, if needed, should be adjusted to maintain clinical euthyroidism, guided by free thyroxine levels.