Abstract Introduction: Periampullary adenocarcinoma (PAC) is a less frequent tumor accounting for approximately 0.5%–2% of all gastrointestinal malignancies. Histologically, PAC subtyped into intestinal and pancreaticobiliary adenocarcinoma which is further confirmed by immunohistochemistry (IHC). Subtyping of PAC has emerged as an important prognostic factor with potential therapeutic implications. Aim: The aim of the study was to assess morphology and IHC expression of CK7, CK20, and CDX2 to subtype PAC and correlate the subtype predicted on histomorphology with the immunohistochemical expression. Materials and Methods: This was a cross-sectional study done from January 2018 to July 2023. A total of 28 pancreaticoduodenectomy specimens were assessed and further classified into intestinal and pancreaticobiliary subtypes after correlating both histological and immunohistochemical features. Statistical analysis was performed using the standard statistical software. P <0.05 was considered statistically significant. Results: Histomorphology and IHC (CK7, CK20, and CDX2) expression was studied in 28 cases having an age range from 41 to 74 years including 18 males. Based on histomorphological findings, they are categorized into intestinal (n = 15) and pancreaticobiliary (n = 13) subtypes. The use of only morphology showed a sensitivity, specificity, and diagnostic accuracy of 63.6%, 52.9%, and 53.16%, respectively, for the intestinal subtype and 50%, 57%, and 57%, respectively, for the pancreaticobiliary subtype. With the use of combined histomorphology and IHC the sensitivity, specificity, and diagnostic accuracy was >90% with a significant reduction in false-positive diagnosis. Conclusion: The correlation of histomorphology and IHC findings can aid in better subtyping of PAC.