Herpes zoster infection may herald the presence of a hidden malignancy. We encountered a case of a carcinoma of the ampulla of Vater in a 72-year-old female in which the ampullary lesion was found during a work-up for excluding certain causes of Herpes zoster infection. An esophagogastroduodenoscopy showed a polypoid mass at the ampulla of Vater. A pylorus-preserving pancreaticoduodenectomy was performed and the pathology of the resected specimen confirmed well differentiated adenocarcinoma in the background of villous adenoma. The stage of the tumor was T2N0M0. This case illustrates that it may be necessary to do some diagnostic work-ups in patients with Herpes zoster infection to exclude underlying diseases. However, the extent of the work-ups should be determined in the future based on the cost-effectiveness data.