The intestine-specific caudal-related homeobox transcription factor Cdx2 is widely accepted to play a key role in intestinal development and differentiation in mammals. We studied the role of Cdx2 in the development of Barrett's esophagus (BE). In previous studies, we have shown a sequence of morphological changes of squamous epithelium leading to BE, found a peculiar metaplastic change common to other parts of gut, and proposed the concept of a "gut regenerative cell lineage" (GRCL). The GRCL is characterized by pyloric-foveolar metaplasia with goblet cell metaplasia, which occurs in the regenerative process in response to chronic inflammation. BE very likely develops through the GRCL, and we studied the expression of Cdx2 in various lesions of rat esophageal mucosa induced by duodenal reflux, using reverse transciptase-polymerase chain reaction and immunohistochemistry against Cdx2. We found that Cdx2 was expressed not only in specialized columnar epithelium (SCE) of BE, but also in several pyloric gland and foveolar metaplastic cells which developed in the basal layer of the squamous epithelium at an earlier stage of SCE development. These findings indicate that Cdx2 plays a crucial role in directing intestinal-type differentiation of the GRCL.