Extra-ampullary duodenal adenocarcinomas are rare, and when studied, frequently have been grouped with jejunoileal adenocarcinomas. Nevertheless, anecdotal experiences suggest that these neoplasms may present 2 or more distinct phenotypes. To better characterize these neoplasms, we performed a retrospective review of 38 cases with a special focus on the morphologic and immunophenotypic characteristics and their clinicopathologic significance. Our cohort of extra-ampullary duodenal adenocarcinomas was classified on the basis of the morphologic features into gastric type (n=19, 50%), intestinal type (n=14, 37%), pancreaticobiliary type (n=2, 5%), and others (n=3, 8%). Most gastric-type adenocarcinomas (n=18, 95%) developed in the proximal duodenum, whereas the other types were located equally in the proximal and distal duodenum. Intestinal-type dysplasia was present at the periphery of 8 (57%) intestinal-type adenocarcinomas, and 8 (42%) gastric-type adenocarcinoma were associated with gastric-type dysplasia. Gastric foveolar metaplasia (n=12) and Brunner gland hyperplasia (n=10) were exclusively recognized adjacent to gastric-type adenocarcinomas. Notably, intestinal-type histology and the absence of lymph node metastasis were significantly associated with favorable disease-free survival in univariate and multivariate analyses. In summary, this study demonstrated that 2 major subsets of extra-ampullary duodenal adenocarcinoma, intestinal type and gastric type, are associated with distinct histopathologic features and clinical behavior.