We herein report a rare case of primary mucinous carcinoma of the duodenum associated with hereditary nonpolyposis colorectal cancer (HNPCC). A 50-year-old man known to have HNPCC based on the Amsterdam criteria I was admitted because of the presence of a duodenal tumor. Duodenoscopy revealed an ulcerated tumor in the posterior wall of the second portion of the duodenum and the malignancy was confirmed by a biopsy. He underwent a pylorus-preserving pancreaticoduodenectomy with a regional lymph node dissection. The histological diagnosis was mucinous carcinoma of the duodenum with lymph node metastasis. High-frequency microsatellite instability (MSI-H) was identified in both the colon and a duodenal specimen based on a microsatellite assay. A germline mutation in the hMSH2 gene was also identified. Even though extracolonic malignancies are associated with HNPCC, duodenal cancer is nevertheless very rare, and only two cases have been reported over the past 20 years. The present case is therefore only the third such case and the patient is herein described with a brief review of the literature.