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Enteritis cystica profunda (ECP), a rare and benign condition, is defined as the displacement of the glandular epithelium into the submucosa and more profound layers of the small intestinal wall leading to the formation of mucin-filled cystic spaces. ECP frequently occurs in the ileum or jejunum and is associated with diseases such as Crohn disease and Peutz-Jeghers syndrome. ECP also develops in the absence of known pathology. ECP in the duodenum is very rare and mostly occurs without associated conditions. In this report, we present a rare case of ECP without an associated disease, in the second portion of the duodenum distal to the ampulla of Vater and coexisting with lipoma within the polypoid lesion.