Periampullary adenocarcinomas (PAC) are rare malignant tumors with worst survival rates due to destructive route of the disease. It comprises distal bile duct, pancreatic, ampullary and duodenal adenocarcinoma that originate within periampullary complex. The primary origin of PAC in this area is often difficult previous to the surgery into pancreaticobiliary (PB-PAC), intestinal (I-PAC) and mixed type (MT-PAC) as PB-PAC carries bad prognosis. Objective:The main aim was to study the histomorphological features and immunohistochemical (IHC) expression of Cytokeratin (CK) 7 and 20 in PAC and assess their expression with known histopathological prognostic parameters. Method: A total number of 31 resected pancreatoduodenectomy specimens were studied in the department of Pathology, in a tertiary care center, Karnataka, India for histomorphological features with CK7 and CK 20 expression. All the statistical methods were carried out through the SPSS for Windows (version 22.0). A p-value of ≤0.05 was taken to be statistically significant. Results: The cases were categorized into PB-PAC (CK7+), I-PAC (CK20+) and MT-PAC (CK7+ and CK20+) based on histomorphological and histomolecular typing. There was a positive association between histomorphology and histomolecular typing. The difference in the proportion of histomolecular profiling between the expressions was statistically significant with p-value of ≤0.001. Conclusions: The concordance in PB-PAC, I-PAC and MT-PAC by usual haematoxylin and eosin microscopy and later confirmed by the immunophenotyping advocates sub typing to be incorporated in the routine histopathology report. The importance of correctly categorizing of the PB-PAC, I-PAC and MT-PAC is mainly for the prognosis and difference in administering of the targeted chemotherapy regimens. Key Words: Adenocarcinoma, CK7, CK20, Pancreaticobiliary, Periampullary reg