AIM: To evaluate esophageal mucosal defense mechanisms at an epithelial level to establish if pantoprazole treatment can induce ultrastructural healing and improvement in the proliferation activity of the esophageal epithelium in gastroesophageal reflux disease (GERD). METHODS: This was a single-blinded study for pHmonitoring, and histological, ultrastructural and MIB1 immunostaining evaluation. Fifty eight patients with GERD were enrolled and underwent 24 h pH-monitoring and endoscopy. Patients were treated for 12 and 24 mo with pantoprazole. Esophageal specimens were taken for histological and ultrastructural evaluation, before and after the treatment. RESULTS: With transmission electron microscopy, all patients with GERD showed ultrastructural signs of damage with dilation of intercellular spaces (DIS). After 3 mo of therapy the mean DIS values showed asignificant reduction and the mean MIB1-LI values of GERD showed an increase in cell proliferation. A further 3 mo of therapy significantly increased cell proliferation only in the erosive esophagitis (ERD) group. CONCLUSION: Three months of pantoprazole therapy induced ultrastructural healing of mucosal damage in 89% and 93% of ERD and non-erosion patients, respectively. Moreover, long-term pantoprazole treatment may be helpful in increasing the capability for esophageal cell proliferation in GERD, particularly in ERD patients. AIM: To evaluate esophageal mucosal defense mechanisms at an epithelial level to establish if pantoprazole treatment can induce ultrastructural healing and improvement in the proliferation activity of the esophageal epithelium in gastroesophageal reflux disease (GERD). METHODS: This was a single-blinded study for pH monitoring , and histological, ultrastructural and MIB1 immunostaining evaluation. Fifty eight patients with GERD were enrolled and underwent 24 h pH-monitoring and endoscopy. Patients were treated for 12 and 24 mo with pantoprazole. Esophageal specimens were taken for histological and ultrastructural evaluation, before and after the treatment. RESULTS: With transmission electron microscopy, all patients with GERD showed ultrastructural signs of damage with dilation of intercellular spaces (DIS). After 3 mo of therapy the mean DIS values ​​showed asificant reduction and the mean MIB1-LI values ​​of GERD showed an increase in cell proliferation. A further 3 mo of therapy signif CONCLUSION: Three-month of pantoprazole therapy induced ultrastructural healing of mucosal damage in 89% and 93% of ERD and non-erosion patients, respectively. Moreover, long-term pantoprazole treatment may be helpful in increasing the capability for esophageal cell proliferation in GERD, particularly in ERD patients.