Primary hypothyroidism is associated with hypertrophy and hyperplasia of thyrotropic cells. In addition, pituitary adenomas that produce thyroid-stimulating hormone occur in both hypothyroidism and hyperthyroidism. The relationship between thyrotropic hyperplasia and adenoma formation is, however, unsettled. We summarize the results of a histologic and immunocytologic study of the pituitary glands of 64 patients with long-standing primary hypothyroidism in an effort to characterize the changes in thyrotropic cells as related to the duration and severity of disease, to therapy, and to the development of thyrotropic adenomas. Diffuse and nodular thyrotropic cell hyperplasia was noted in 69% and 25% of glands, respectively. A crude correlation was observed between the degree of thyrotropic cell hyperplasia and the relative lack of thyroid hormone replacement therapy. In 12% of glands, tumorlet formation was observed, perhaps representing an intermediate stage between nodular hyperplasia and the development of microadenoma. Twelve adenomas were noted, five of which contained thyroid-stimulating hormone immuno-reactive cells. Although thyroid hormone deficiency seemed to selectively affect thyrotropic cells, lactotropic hyperplasia was observed in 20% of patients; the mechanism accounting for prolactin cell hyperplasia remains obscure.