Background and aims: Gastroesophageal reflux disease (GERD) is a common disorder and could be a risk factor for esophageal cancer. Many molecular changes occur in esophageal carcinogenesis; however, the exact molecular pathway in development of adenocarcinoma is unknown. Our aim is to evaluate prevalence of two potential biomarkers (p53 and ki67) in the multistep carcinogenesis process in patients with GERD. Methods: We investigated 203 patients with GERD analyzing the immunoexpression of p53 and ki67 (MIB-1) in biopsy specimens obtained by endoscopy, from patients with normal esophageal mucosa, esophagitis, columnar epithelium in distal esophagus and adenocarcinoma. The patients were distributed into four groups according to the histological diagnosis : Group 1: normal squamous epithelium (60), Group 2: chronic oesophagitis (83), Group 3: columnar epithelium in distal esophagus (with or without intestinal metaplasia) (45), Group 4: adenocarcinoma (15) Results: p53 immunoexpression was present in 11.6% in G1, 38.5% in G2, 51% in G3 and 53.3% in G4 (p<0.01%). The rate of Ki67 immunoexpression also increased according with the severity of the histological diagnosis, G1=21.1%, G2=39.4%, G3 47.8%, G4= 63.7% (p<0.001). We observed an association between the severity of histological alterations and the likelihood of ki67 and p53 expression. We observed a linear progressive correlation from normal squamous epithelium to adenocarcinoma of both biomarkers (p<0.05 - ANOVA and Chi-square for trend). Conclusions: p53 and ki67 expression may be one of the useful biomarkers for assessing the risk of progression to esophageal cancer in patients with GERD. Proliferative alterations measured by Ki67 (MIB-1) could be associated with molecular changes assessed by p53.