Increased understanding of the molecular processes associated with the dysplasia-adenocarcinoma sequence linked to Barrett's esophagus may be beneficial for early tumor detection and refined diagnosis as well as for improved prognostication. We applied immunohistochemical staining for the markers Ki-67, p53, beta-catenin and E-cadherin in order to evaluate their prognostic importance in 59 Barrett's esophagus-associated adenocarcinomas. Reduced or absent membranous E-cadherin staining was identified in 75% of the tumors and predicted poor prognosis in manova (hazard ratio [HR] 3.3, P = 0.05). The small subset of tumors with low levels (< 10%) of Ki-67 staining showed a worse prognosis (HR 3.2, P < 0.01), whereas immunostaining for p53 and beta-catenin showed no correlation with prognosis. Deranged cell adhesion has been demonstrated to be an early event in tumor development. The down-regulation of E-cadherin and its prognostic importance indicate that cell adhesion may be a prime area for targeted therapies in esophageal adenocarcinoma.