The incidence of spontaneous pituitary nodules in rats increases progressively with age. In a colony of male Long-Evans rats, 50 per cent of the 2- to 3-year-old animals harbored pituitary nodules which were composed almost exclusively of sparsely granulated prolactin (PRL) cells. Sixty per cent of the PRL nodules were multicentric and in most instances were associated with diffuse hyperplasia of PRL cells adjacent to the nodules. A progressive increase with age in the population of PRL cells was also observed. These findings suggest that the pituitary nodules may have originated from foci of PRL hyperplasia. Furthermore, five of these glands contained additional nodules of other hormonal cell types, including mixed PRL/gonadotropins (two animals), mixed PRL/thyrotropin-stimulating hormone (one), gonadotropins (one), and adrenocorticotropic hormone (one). These animals also demonstrated a high incidence of thyroidal C cell nodular hyperplasia and/or medullary thyroid carcinoma (42 per cent), adrenal medullar nodules (31 per cent), and parathyroid nodular hyperplasia (30 per cent). In human kindreds with multiple endocrine neoplasia syndromes, concomitant thyroidal C cell and adrenal medullary proliferative lesions, as well as parathyroid abnormalities, are found in type II phenotype patients, whereas pituitary, pancreatic islet, and parathyroid abnormalities develop in patients with type I phenotype. The Long-Evans rat strain, with concomitant proliferative lesions in these four endocrine organs, may provide a useful model system of a mixed multiple endocrine neoplasia syndrome and, also, of prolactin-secreting pituitary adenomas.