The pathogenesis of duodenal adenomas is not well elucidated. Much of the literature pertains to ampullary adenomas and those associated with familial adenomatous polyposis (FAP). In this study, we evaluated the molecular features of a series of sporadic duodenal adenomas (n=22) that developed distal to the ampulla, and compared them with the features of sporadic ampullary adenomas (n=9) and FAP-related polyps (n=12). Using a combination of immunohistochemical studies [cytokeratins 7 and 20, E-cadherin, beta-catenin, p53, MLH-1, MSH-2, MSH-6, and O6-methylguanine methyltransferase (MGMT)], DNA sequencing [beta-catenin, adenomatous polyposis coli (APC), p53, KRAS, and BRAF], and a polymerase chain reaction-based microsatellite instability assay; we assessed each case for abnormalities in the Wnt signaling and mitogen-activated protein kinase pathways and DNA repair mechanisms. Wnt signaling pathway abnormalities occurred in sporadic, nonampullary (82%), and ampullary (77%) adenomas at comparable rates, usually reflecting nuclear beta-catenin immunostaining (64% and 44%, respectively), and APC rather than beta-catenin, mutations. KRAS mutations were infrequent in sporadic, nonampullary adenomas (18%), and FAP-related adenomas (9%); moderately frequent in ampullary adenomas (44%); and none of the cases harbored BRAF mutations. Only 4 (13%) sporadic adenomas showed nuclear p53 staining, but no p53 mutations were detected in exons 5 to 8. Loss of O-methylguanine methyltransferase immunostaining was identified in 1 sporadic, nonampullary adenoma, and none of the polyps in any group showed loss of MLH-1, MSH-2, or MSH-6 staining, or high-frequency microsatellite instability. We conclude that sporadic and FAP-related adenomas show similar molecular features, regardless of their anatomic location. Similar to colorectal adenomas, they harbor APC and KRAS mutations; but BRAF mutations, p53 alterations, and DNA mismatch repair abnormalities are rare.