The purpose of this study was to clarify the role of orotate phosphoribosyltransferase (OPRT) in the progression of hepatobiliary and pancreatic carcinomas. Representative sections from 8 surgically resected pancreatic carcinomas, 5 gallbladder carcinomas and 19 hepatocellular carcinomas (HCCs) were examined microscopically. Sites of pancreatic intraepithelial neoplasia (PanIN) were counted, and histologic subtypes of invasive ductal carcinoma of the pancreas (IDC) were determined. Gallbladder carcinomas and HCCs were examined histologically, and the subtypes and spread patterns were assessed. Expression of OPRT was examined immunohistochemically. A total of 75 PanINs were identified. Expression of OPRT increased as lesions progressed from early to high-grade PanINs (PanIN-1A and -1B versus PanIN-2 and -3, p=0.0004). Three (37.5%) of the 8 pancreatic IDCs were positive for OPRT. In the remaining 5 cases, OPRT was expressed only in the neoplastic ducts adjacent to PanIN-3s. In gallbladder carcinomas, mucosal neoplastic epithelium showed dense cytoplasmic expression in 4 of the 5 cases, but expression was absent in the deeply invasive lesions. Among HCCs, 15 of the 19 cases were negative for OPRT in the central area of the tumor, but 8 of the 19 cases expressed OPRT in vascularly invasive lesions. Our data suggest that OPRT is involved in early events of pancreatic and gallbladder carcinogenesis and invasion of HCC.