It has been proposed recently that gastroesophageal reflux disease (GERD) patients may be categorized into three distinct groups exhibiting non-erosive reflux disease (NERD), erosive reflux disease (ERD), and Barrett's esophagus (BE). Measurement of relative gene expression levels was undertaken to identify distinct molecular subclasses in different variants of gastroesophageal disease. The measurements were made with Affymetrix U133A 2.0 GeneChips and RNA isolated from mucosal samples of normal squamous esophageal epithelium from 24, 28, and 26 patients with NERD, ERD and BE, respectively. Statistical testing of microarray data showed that gene expression profiles are discriminative for BE and NERD, but not for combinations of BE and ERD or NERD and ERD. In addition, women developing NERD exhibited transcriptional patterns that differed from those of men with BE. In clustering analyses, we did not observe correlations between sex and assignment of gene expression profile of ERD patients to either the NERD or the BE group. Although the biological significance of the identified genes remains uncertain, we hypothesize that GERD is a monophyletic disease that develops with the onset of gastroesophageal reflux and represents two main molecular classes, which may result in different progressions to inflammatory process within esophageal epithelium modulated by sexual dimorphism. While normal epithelium samples from NERD and BE patients are molecularly homogeneous, esophageal mucosa from ERD patients is molecularly similar to either NERD or BE. These findings may be useful for defining molecular markers which could predict potential progression to Barrett's metaplasia among patients with reflux disease.