Purpose: Oxidative stress is related to the carcinogenic pathway of reflux esophagitis to Barrett's metaplasia to esophageal adenocarcinoma (EAC). Recent studies have shown that a decreased manganese superoxide dismutase (MnSOD) level is associated with the increased incidences of Barrett's esophagus (BE) and EAC. The aim of this study was to investigate MnSOD supplementation as a chemopreventive agent to prevent oxidative injury and subsequent BE and EAC formation. Experimental Design: Our esophagoduodenal anastomotic (EDA) model was done on rats according to our established procedure and treated with Mn(III)tetrakis(4-benzoic acid) porphyrin (MnTBAP; 10 mg/kg, i.p. every 3 days). Histologic changes were determined after the EDA model at 1, 3, and 6 months. Lipid peroxidation and 8-hydroxy-deoxyguanosine for DNA oxidative damage were determined by thiobarbituric acid^reactive substance assay and immunohistochemical staining. Enzymatic activities of MnSOD and Cu/ZnSOD were evaluated, and the rate of proliferation was determined by proliferating cell nuclear antigen staining. Results: Severe esophagitis was seen in 100% of the EDA rats, and morphologic transformation within the esophageal epithelium was observed with intestinal metaplasia (40% of animals) and cancer (40% of animals) identified after 3 months. Decreased oxidative damage, along with the decreased degree of esophagitis and incidence of BE (20%) and EAC (0%), was found in MnTBAP-treated EDA rats comparing with the saline-treated EDA control. Decreased proliferation (46%) and increased SOD enzymatic activities (25%) were also found in the EDA rats treated with MnTBAP. Conclusion: MnTBAP protected rat esophageal epithelium from oxidative injury induced by EDA, and it could prevent the transformation of esophageal epithelial cell to BE to EAC by preservation of antioxidants.Esophageal adenocarcinoma (EAC) has received considerable attention because of the dramatically increased incidence in the past 2 decades and the poor prognoses with a 5-year survival rate of 10% to 20% (1 -5). Currently, it is widely accepted that a cause-effect relationship exists between gastroesophageal reflux disease and EAC. Oxidative stress has been proposed to be closely related to the carcinogenic progression of reflux esophagitis, Barrett's metaplasia, and EAC. It has been shown that reactive oxygen species increase with the grade of reflux esophagitis and are highest in Barrett's esophagus (BE) in clinical patients (6). Several studies have also shown that reactive oxygen species cause DNA injury, such as strand breakage, alterations in guanine and thymine bases, and DNA cross-linkage (7,8). Therefore, oxidative DNA damage may contribute to the accumulation of genetic damage, and the accumulation of genetic and epigenetic aberrations produces one or more clones with metaplastic and/or malignant potential (9).In our previous studies using an external esophageal perfusion rat model (10 -13), we have shown significant increased levels of lipid peroxidation and 8-hydr...