Introduction: Von Hippel Lindau (VHL) disease is a hereditary disorder characterized by the development of benign or malignant tumors in the brain, spinal cord, eyes, adrenal medulla, kidney, pancreas, and many other organs. Advances in molecular diagnosis have led to the identification of the affected members of families at earlier stages. We present the clinical, laboratory, and genetic characteristics of five generations of large Iranian kindred with VHL. Case Presentation: The proband, a 52-year-old Iranian man, was recognized with VHL. All family members underwent clinical, laboratory, imaging, and genetic evaluation. Medical files and histopathology reports of patients who had been operated on before were also reviewed. Diagnosis of the disease was based on clinical findings, positive family history of VHL, and development of a central nervous system or retinal hemangioblastoma or pheochromocytoma. Based on diagnostic criteria, our initial evaluations revealed that 10 members of the family had already been affected by the disease. Among them, nine had pheochromocytoma, and one had retinal hemangioblastoma. There was no case of kidney tumors among the kindred. Conclusions: Study results show the high penetrance of the disease and focus on the large burden imposed by the disease on the health and quality of life of patients afflicted with the disease, emphasizing the importance of surveillance from early childhood for detection and management of the disease as early as possible.