We performed a clinicopathologic analysis of 74 periampullary and duodenal adenomas from 30 patients with familial adenomatous polyposis to evaluate the growth pattern, mucin histochemical profile, and degree and significance of Paneth cell and endocrine cell differentiation in these lesions. A trend toward more numerous adenomas was seen in patients with the longest intervals since their previous colectomies. Adenomas were most often clustered in the periampullary region and were numerous (> 20) in 40% of patients. Periampullary and duodenal adenomas were morphologically similar; both exhibited the same size-villous shape-dysplasia relationship as sporadic and familial adenomatous polyposis-associated colonic adenomas. Adenomas showed a heterogenous pattern of mucin production (mixed small intestinal-large intestinal types), with a shift toward the colonic type (sulfomucin) in lesions that were larger, villous, or severely dysplastic. Ninety-two percent of adenomas showed Paneth cell differentiation (average n Paneth cells/high power field = 24.5), and 99% showed endocrine cell differentiation (average n endocrine cells/high power field = 64.4). In general, the proportion of these specialized cell types was inversely related to size, villous shape, and degree of epithelial dysplasia. These results suggest that periampullary and duodenal adenomas in familial adenomatous polyposis arise from the neoplastic transformation of an undifferentiated stem cell that retains its ability for multidirectional differentiation.