Histological subtyping of periampullary carcinomas is considered as a criterion for prognosis and therapeutic implications of these tumours. We assessed the immunoexpression rates of HepPar-1, CDX2 and MUC2 antibodies in different subtypes of periampullary adenocarcinomas (PAC), intestinal and pancreatobiliary, in order to assess their impact on differential diagnosis of this group of cancers. The expression of antibodies was also measured in ductal adenocarcinoma of the pancreatic head (DAPH).Sixty-five patients with PAC and DAPH who underwent pancreatic Whipple resection constituted the study cohort. Of these, 46 (71%) had PAC, and 19 (29%) had DAPH. Among PACs, 20 (44%) were intestinal and 26 (56%) were pancreatobiliary type.HepPar-1 immunoreactivity was detected in 18 (39%) of all PACs. The rate of HepPar-1 expression was significantly higher in intestinal type PAC (75%) than it was in pancreatobiliary type (12%). The sensitivity, specificity, and accuracy of HepPar-1 immunoexpression for diagnosing intestinal type PAC were 75% , 89%, and 83%, respectively. Similarly, the rates of both CDX2 and MUC2 expressions were significantly higher in intestinal type PAC (80%) than they were in pancreatobiliary type (8%). The sensitivity, specificity, and accuracy of both CDX2 and MUC2 immunoexpressions for intestinal type PAC were 80%, 92%, and 87%, respectively.HepPar-1 antibody was found to be a highly sensitive and specific marker for distinguishing intestinal type from pancreatobiliary type among PACs. In addition to CDX2 and MUC2 antibodies, HepPar-1 immunoexpression seems to have a potential role in differential diagnosis of PACs.