Barrett’s esophagus (BE) is the precursor to esophageal adenocarcinoma. A major challenge is identifying the small group with BE who will progress to advanced disease from the many who will not. Assessment of p53 status has promise as a predictive biomarker, but analytic limitations and lack of validation have precluded its use. The aim of this study was to develop a robust criteria for grading abnormal immunohistochemical (IHC) expression of p53 and to test its utility as a biomarker for progression in BE.