Multinucleated epithelial giant cells mimicking viropathic effect or dysplasia have been documented in the gastrointestinal tract, specifically in the esophagus and colorectal polyps. This finding has been associated with either inflammation or hyperplasia in prior case series. The authors report the first occurrence in the small intestine involving a 30-year-old woman without a coexisting inflammatory or hyperplastic process. The multinucleated epithelial giant cells featured numerous homogenous nulei (mean 9 nuclei, range 5-18) limited to duodenal villi. Immunohistochemistry revealed strong positivity for cytokeratin AE1/AE3 and negativity for herpes simplex virus 1 and 2, varicella simplex virus, and cytomegalovirus. In situ hybridizations for adenovirus and Epstein-Barr virus were also negative. Despite a lack of a specific etiologic agent, evidence suggests multinucleated epithelial giant cells are the consequence of inflammation, chronic injury, or cellular degeneration.