Periampullary carcinoma (PC) is classified into intestinal and pancreatobiliary subtypes using morphology and immunohistochemistry (IHC). Different combinations of markers have been used in the literature. One hundred eight PCs were classified using morphology and IHC (CDX2, mucin [MUC] 2, cytokeratin [CK] 20, CK7, CK17, and MUC1). The expression of these markers was compared with different histologic subtypes, histopathologic prognostic parameters, and patients' survival. There were 38 intestinal and 53 pancreatobiliary subtypes classified on morphology alone. CDX2 showed high sensitivity (89.5%) and specificity (100%) for intestinal type. CK20 and MUC2 showed low sensitivity (50% and 39.5%) but high specificity (86.8% and 96.2%) for intestinal type. CK7 and CK17 showed a sensitivity of 90.5% and 32% and a specificity of 21% and 89.4%, respectively, for pancreatobiliary subtype. MUC1 was 100% sensitive but 0% specific in pancreatobiliary subtype. The overall median survival in morphologic and IHC intestinal type was 45 months versus 20 months in pancreatobiliary type (P = 0.01). Intestinal and pancreatobiliary types of PC were differentiated in 84.2% of cases by morphology alone and in 87.9% cases with IHC. CDX2-positive tumors had a median survival of 44 months versus 22 months in CDX2-negative tumors (P = .03). IHC helped in reclassifying an additional 4 cases of mixed and other types. Among the panel used, CDX2 showed a high sensitivity and specificity for intestinal subtype and was an independent prognostic marker for longer survival. Thus, CDX2 may be used routinely with morphology in subtyping of PC, and a panel of markers may be used in morphologically difficult cases.