Intensive proteinuria accompanied by marked renal enlargement occurs in rats bearing functioning pituitary tumor MtT SA5. Urinalysis showed that protein excretion was up to 700 mg/day, and that the excreted protein consisted mostly of albumin. However, serum total protein and albumin levels remained almost unchanged. Histological examination revealed glomerular lesions, hyaline casts in the tubules, and proliferation of the tubular epithelium. The glomerular lesions consisted of accumulation of proteinaceous material in the subcapsular space; its organization and formation of fibrous crescents was with or without epithelial crescents. Electron microscopy revealed loss of foot processes and accumulation of absorption droplets in glomerular epithelial cells. Removal of the tumor resulted in a rapid reduction in urinary protein excretion. However, proteinuria persisted for at least 4 weeks after tumor removal with levels of approximately one-fourth of those before tumor removal. Histological changes of the kidneys resolved to some extent but damage still remained in the glomerular epithelial cells 4 weeks after tumor removal. Although proteinuria in animals bearing functioning pituitary tumors has long been implicated in hyperprolactinemia, the present study suggests that proteinuria in tumor-bearing rats is a control mechanism for overproduction of albumin in the liver stimulated by elevated serum growth hormone since hyperalbuminemia and possibly the hyperfibrinogenemia would cause the elevation of blood viscosity, resulting in thrombosis, unless control mechanisms were present. This proteinuria may serve for studies of glomerular permeability disorders as a model for homologous protein-overload proteinuria.