Inflammation of the gastric cardia, which is the most proximal portion of the stomach, in most instances is the result of either gastroesophageal reflux disease or H. pylori infection. Histologic distinction between these two entities is important because the treatment, natural history, and risk of malignancy are different. Moreover, multilayered epithelium, a possible precursor to Barrett's esophagus, has only recently been described in the gastric cardia, and its relationship to gastroesophageal reflux disease is unknown. The aim of this study was to compare the histologic features of the gastric cardia and the prevalence of multilayered epithelium in patients with reflux versus H. pylori-associated carditis. Routinely processed hematoxylin and eosin-stained mucosal biopsies of the gastric cardia from 30 patients with reflux-associated carditis, 25 with H. pylori-associated carditis, and 30 control patients (no reflux, no H. pylori) were evaluated for a wide variety of histologic features such as goblet cell metaplasia, presence of multilayered epithelium, type of glandular epithelium (mucous, oxyntic, mixed mucous/oxyntic), pancreatic metaplasia, overall degree of inflammation, and the quantity of individual types of inflammatory cells. The clinical and histologic features were compared between the two study groups and controls. Clinically, the reflux carditis group (male/female ratio: 21/9, mean age 56 years) had a significantly higher male/female ratio (p <0.01) and a slightly higher mean age in comparison with the H. pylori group (male/female ratio: 9/16, mean age 50 years). Histologically, the reflux group had significantly less overall inflammation (p <0.05), with fewer plasma cells (p <0.04) and neutrophils (p <0.006), but a higher prevalence of multilayered epithelium [9 of 30 (30%) vs 1 of 25 (4%) in the H. pylori group, p = 0.01]. In the reflux carditis group, multilayered epithelium was significantly associated with neutrophilic inflammation (p <0.05), but not any other features of chronic carditis or with any of the specific epithelial cell types. The control group showed less inflammatory activity in comparison with the H. pylori group and a lower prevalence of multilayered epithelium and eosinophilic inflammation in comparison with the reflux group. The clinical and pathologic features of reflux carditis are distinct from H. pylori carditis and are characterized by less overall inflammation and fewer neutrophils and plasma cells. Multilayered epithelium not uncommonly occurs in the cardia of patients with gastroesophageal reflux disease but without Barrett's esophagus, further supporting our hypothesis that multilayered epithelium may represent an early precursor in the development of columnar metaplasia in Barrett's esophagus.