The diagnosis of epithelial dysplasia and subsequent grading of the dysplasia in Barrett's esophagus (BE) are clinically significant for the patient's follow-up and management. However, histologic diagnosis for these lesions often proves challenging for general practicing pathologists and even GI pathologists. Certain biomarkers, such as p53 and racemase, have shown some value in diagnosing these lesions. We previously showed that SIRT1, the mammalian homologue of silent mating type information regulator 2 in budding yeasts, was over-expressed in colonic adenomas. The goal of this study was to investigate the value of SIRT1 in BE-related dysplasia. Twenty BE cases without epithelial dysplasia, 11 with low-grade dysplasia, 4 with high-grade dysplasia, and 8 invasive carcinomas were included in this study. Twenty-nine of 31 cases with no epithelial dysplasia or low-grade dysplasia showed weak nuclear staining at the base of the crypts, but the surface epithelium was negative in all cases. Ten of twelve cases with high-grade dysplasia or carcinomas had 2-3+ diffuse nuclear staining including the surface epithelium. Using 2+ surface nuclear staining as the cutoff, BE with high-grade dysplasia and carcinoma had significantly higher SIRT1 expression than BE with no dysplasia or low-grade dysplasia (p=0.0001). Therefore, SIRT1 appears to be a very promising biomarker in the diagnosis of BE with high-grade dysplasia and carcinoma. This is the first report using SIRT1 as an adjunctive marker on evaluation of BE-related dysplasia, but large-scale and prospective studies are needed to confirm and validate our findings.