BACKGROUND AND AIM Acid suppressive therapy has been reported to regress Barrett's esophagus. However, it is still controversial as to whether all Barrett's esophagus patients respond to this therapy. The factors that might facilitate newly developed squamous re-epithelialization after biopsy excision of Barrett's mucosa were evaluated to identity individuals who may favorably respond to the regression therapy. METHODS Two hundred and forty-seven biopsy sites from 185 patients with Barrett's esophagus were examined by endoscopy to investigate possible squamous re-epithelialization of Barrett's mucosa after endoscopic biopsy. Before endoscopic examination, all participants were requested to answer questionnaires concerning sociodemographic characteristics, lifestyle habits and drugs usage. The mucin phenotype, Cdx2 expression, cyclooxygenase-2 expression, cellular proliferation and apoptosis of Barrett's mucosa were immunohistochemically investigated in the biopsy samples taken from Barrett's esophagus. The influence of these factors on the newly developed squamous re-epithelialization of Barrett's mucosa after endoscopic biopsy excision was evaluated. RESULTS By multivariate analysis, the independent factors that favored squamous re-epithelialization were the gastric mucin predominant phenotype of Barrett's mucosa and the absence of Cdx2 protein expression. In Barrett's mucosa with the gastric predominant mucin phenotype, proton pump inhibitor administration, the absence of reflux esophagitis and a low proliferating cell nuclear antigen index were found to be independent predictors for squamous re-epithelialization. CONCLUSIONS The absence of the intestinal predominant mucin phenotype was a positive predictor for newly developed squamous re-epithelialization at the site of biopsy of Barrett's mucosa. Only Barrett's esophagus with the gastric predominant mucin phenotype may predict a favorable response to acid suppressive therapy.