A 42-year-old male presented to our hospital with a history of anorexia and weight loss of 6 kg in 3 mo. Esophagogastroduodenoscopy revealed a huge mass located on the second portion of duodenum with mild stenosis. The pathology of endoscopic biopsy was low grade dysplasia. Imaging examinations showed duodenal cancer with invasion to common bile duct and pancreas. We suspected duodenal carcinoma and performed pancreato-duodenectomy. Adenocarcinoma arising from a heterotopic pancreas at the second portion of the duodenum was finally diagnosed by immunohistochemical staining. Malignant transformation in the duodenum arising from a heterotopic pancreas is extremely rare. Herein, we describe the case of adenocarcinoma arising from a heterotopic pancreas, which was located in the second portion of the duodenum, with a review of the literature.