Long segment Barrett's esophagus (LSBE) is a recognized risk factor for the development of esophageal dysplasia and carcinoma. However, the risk of dysplasia arising within intestinal metaplasia below a normal-appearing Z-line (i.e., in native cardiac mucosa) is unknown. Regular endoscopic surveillance is required in patients with LSBE and is frequently performed in short segment BE (SSBE), but the need for surveillance in cardiac intestinal metaplasia (CIM) is unknown. Unfortunately IM arising in SSBE and immediately below a normal Z-line can be indistinguishable histologically on H&E stains. Previous reports suggest that the appearance of superficial CK20 immunohistochemical staining accompanied by intermediate and deep CK7 positivity is characteristic of BE, whereas CIM specimens show superficial and deep CK20 positivity and weak to absent CK7 staining. We hypothesized that CK7/20 immunostaining of metaplastic biopsies from the esophagus and stomach would allow complete differentiation of these two entities when correlated with the endoscopic appearance. We undertook an evaluation of gastric and esophageal specimens to determine whether these characteristics were valid. Cases of both BE (long and short segment) and CIM, as well as cases of gastric cardiac biopsies lacking IM, were evaluated for CK7 and CK20 and correlated with the endoscopic appearance. We observed that, although the "Barrett's" pattern of CK7/20 was maintained for many cases of BE, the sensitivity and specificity were only moderate (65% and 56%, respectively). The pattern of staining for the CIM was variable, i.e., some cases showed a CK7/20 Barrett's pattern despite a normal appearance at endoscopy. The differences between this and previous studies may be due to inaccurate visualization of SSBE on endoscopy, the development of very early SSBE cases, inter-observer variability, fixation differences, or antibody differences. Whatever the cause of the differences, if results between laboratories are not comparable, CK7/20 immunostaining cannot be used to differentiate reliably between IM present in biopsy specimens taken from above versus below the Z-line. However, further studies should be performed to determine whether the presence or absence of a Barrett's pattern of CK7/20 immunostaining could predict progression to dysplasia or carcinoma.