It is important to distinguish Barrett's esophagus (BE) from intestinal metaplasia related to carditis because these conditions have a different natural history, risk of malignancy, and treatment. However, the distinction between these entities is difficult both clinically and pathologically. The aim of this study was to evaluate and compare the immunostaining pattern of five mucin core polypeptides in BE to cases of carditis or antritis with intestinal metaplasia. Routinely processed mucosal biopsies from 22 patients with intestinal-type BE, 24 patients with cardia intestinal metaplasia (10 Helicobacter pylori positive), 17 patients with antral intestinal metaplasia (all H. pylori positive), 20 control patients with a normal antrum, and 22 control patients with a normal cardia were immunostained with monoclonal antibodies against MUC1, MUC2, MUC3, MUC5AC, and MUC6 mucin core polypeptides. Staining was evaluated separately for goblet cells and non-goblet columnar cells and compared between all groups. A significantly higher number of BE cases (P < 0.05) showed goblet cell staining for MUC1 (55%) or MUC6 (32%) compared with patients with carditis with intestinal metaplasia (MUC1 14%, MUC6 7%) or antritis with intestinal metaplasia (MUC1 6%, MUC6 0%). BE also showed a higher frequency of MUC1 and MUC6 positivity in non-goblet columnar cells compared with carditis and antritis cases with intestinal metaplasia. Only cases of BE showed combined MUC1 and MUC6 staining (sensitivity 23%, specificity 100%). The sensitivity and specificity of MUC1 staining for BE are 55% and 96%, respectively, and for MUC6 staining 30% and 96%, respectively. Interestingly, normal gastric cardia mucosa also showed a significantly higher prevalence of MUC2 and MUC3 expression in glandular epithelium (29% and 38%, respectively) compared with the antrum (0% for both markers) (P < 0.05). In conclusion, MUC1 and MUC6 expression in BE is distinct from that of the cardia and antrum with intestinal metaplasia; thus, immunophenotyping for these markers may have some value in a subset of patients in helping to separate BE from patients with intestinal metaplasia of the cardia. Columnar epithelium in the "normal" gastric cardia has a partially intestinalized phenotype and, as a result, may represent an early form of metaplastic epithelium.