The Von-Hippel Lindau (VHL) disease is a rare genetically determined syndrome. Clinical course depends on the occurrence of multiple tumors as central nervous system tumors, phaeochromocytoma and renal cell carcinoma. We describe the second case in the literature reporting about a patient affected by a pancreatic neuroendocrine tumor as the first clinical sign of VHL disease. It has been showed that only a strict follow-up can effectively improve survival. Based on the present case, the follow-up of patients affected by VHL syndrome should routinely include functional tests and imaging exams of the pancreas.