Background and purpose: Ampullary vater carcinoma is a malignant tumor arising in the last centimeter of the common bile duct, but carcinomas originating in the ampulla of Vater by gross inspection can arise from 1 of 4 epithelial types, (1) terminal common bile duct, (2) duodenal mucosa, (3) pancreatic duct, or (4) ampulla of Vater. Distinguishing between true ampullary cancers and periampullary tumors is critical to understanding the biology of these lesions. DPC 4 (Smad 4) is a new tumor suppressor gene frequently inactivated in pancreatic and bile duct adenocarcinoma. DPC4 expression is also suggested as a prognostic in pancreatic cancer. In this study, our aim is to investigate the expression of DPC4 gene in ampullary carcinoma. Materials and Methods: DNA was extracted from ampullary carcinoma, which were resected surgically and histologically selected. Mutations in the genomic sequence of the highly conserved COOH-terminal domain of DPC4 (exons 8-11) was performed by polymerase chain reaction and single-strand conformational polymorphism analysis. Loss of heterozygosity was also analyzed. The products of polymerase chain reaction by original primers were directly sequenced by auto-sequencing (ABI PRISM) and confirmed by the sequence from gene bank. Results: Eight of 48 (16.6%) ampullary carcinomas had point mutations in the DPC4 sequence: 1 in exon 8, 2 in exon 9, and 5 in exon 11. There were 3 silence mutations, 4 missense mutations, and 1 nonsense mutation. CONCLUSIONS: These results suggest that the DPC-4 gene involved in the carcinogenesis in the ampullary carcinoma.