Neuroendocrine tumors of the ampulla of Vater are rare (less than 100 cases reported). We report here a new case characterized by histamine secretion, a hitherto unreported feature. Clinical presentation is similar to that of other tumors of the ampulla of Vater. In our observation, the patient had noticed urticaria on the right forearm for several months. Tumor of the ampulla was confirmed by endoscopic ultrasonography, while neuroendocrine characterization was assessed on biopsies after endoscopic sphincterotomy. Histamine concentration in blood was the only elevated neuroendocrine marker and returned to normal after surgical resection. Histology showed a neuroendocrine tumor with extension to lymph nodes. On immunohistochemical analysis, production of histamine was confirmed, and the diagnosis of mastocytoma was eliminated. In view of the literature, neuroendocrine tumors of the ampulla of Vater are associated with a good prognosis (5 year-survival rate: 90%) despite early lymph node involvement.