von Hippel-Lindau (VHL) disease is an autosomal dominant inherited disorder characterized by extensively vascularized tumors and cysts in specific organs. The VHL gene product plays a critical role in the regulation of transcription elongation by RNA polymerase II. To provide insight into which cells the VHL protein is expressed, we performed immunohistochemistry on human tissue and tumors. The VHL protein was widely expressed in normal human tissue. The cellular distribution of the protein was confined to the cytoplasm of specific cell types. High levels of expression of the protein were observed in neural tissue, especially in Purkinje cells, Golgi type II cells, and dentate nucleus of the cerebellum, pontine nuclei, the inferior olivary nucleus of the medulla oblongata, orthosympathetic ganglia, myenteric, and submucous plexus of the colon. In the other target organs of the VHL disease, high expression was observed in the renal tubule system, the exocrine pancreas, the adrenal cortex, and liver parenchyma. The VHL protein was also expressed in organs not at risk for the disease. The eosinophilic cells of the pituitary gland, epithelial cells of the follicles of the thyroid, epithelial cells of the intestines, bile ducts, and bronchial epithelia showed strong VHL immunoreactivity. Immunohistochemistry did not facilitate the discrimination of tumors obtained from VHL patients or tumors unrelated to the VHL disease. Renal cell carcinomas, hemangioblastomas, and pheochromocytomas, either VHL-related or sporadic, demonstrated positive staining for the VHL protein, which suggests that the antibody also recognizes the mutated VHL protein. The present study suggests a role for the VHL gene that goes beyond the organs involved in the disease. The recognition of cell-specific VHL expression provides a framework for further studies to elucidate the normal function of the VHL gene and to determine its role in specific cell types.