The Barrett’s multistage process is characterized histopathologically by progression from Barrett’s intestinal metaplasia to Barrett’s esophagus with dysplasia and ultimately adenocarcinoma. Understanding of the molecular alterations in this multistage process may contribute to improved diagnosis and treatment. Retinoid X receptors (RXR) play an important role in regulating the morphogenesis, development, growth, and differentiation of cells. Alterations in RXR expression have been observed in a variety of solid tumors; however, the role in Barrett’s esophagus disease has yet to be determined. The aim of this study was to assess the prevalence and timing of RXR messenger RNA expression in the Barrett’s metaplasia-dysplasia-adenocarcinoma sequence and to investigate its role in the development and progression of this disease. We analyzed the mRNA expression of all three RXR subtypes (RXR-alpha, RXR-beta, and RXR-gamma) by using a quantitative real-time reverse transcription-polymerase chain reaction method in 108 specimens from 19 patients with Barrett’s esophagus without carcinoma (BE group), 20 patients with Barrett’s-associated adenocarcinoma (EA group), and a control group of 10 patients without evidence of gastroesophageal reflux disease (CG). RXR-α mRNA expression was significantly decreased (P < 0.001; Kruskal-Wallis test), and RXR-γ was significantly increased (P < 0.001) at higher stages in Barrett’s esophagus. RXR-β expression was highest in Barrett’s tissues and was significantly increased compared to normal squamous tissues (P = 0.01; Wilcoxon test) and adenocarinoma tissues (P = 0.018, Mann-Whitney test). RXR-α and RXR-β mRNA expression was significantly associated in normal squamous esophagus tissues (r² = 0.49; P < 0.001; Spearman test), Barrett’s tissues (r² = 0.63; P < 0.001), and adenocarcinoma tissues (r² = 0.68; P = 0.001). There were significant differences in RXR-α (P = 0.011) and RXR-β (P = 0.005) mRNA expression in histopathologically normal squamous esophagus tissues in patients with cancer and the control group without evidence of gastroesophageal reflux disease. These findings suggest that alterations in the mRNA expression of all three RXR subtypes are frequent events in the development and progression of Barrett’s esophagus and associated adenocarcinoma, that RXR mRNA expression levels may be useful biomarkers for this disease, and that a widespread "field-effect" is present in the normal esophagus of patients with esophageal adenocarcinoma.