Objective: We investigated the relationship between reflux and aberrant deoxyribonucleic acid (DNA) methylation, comparing methylation in the columnar epithelium following successful fundoplication to that in subjects with a failed fundoplication. Summary Background Data: Gastroesophageal reflux is the main risk factor for Barrett esophagus and adenocarcinoma. In these diseases, there is a high level of DNA methylation. Methods: We enrolled 41 patients with Barrett esophagus and a fundoplication at least 5 years earlier for a 24-hour pH study, endoscopy, and collection of biopsies. Biopsies were obtained from 17 Barrett esophagus subjects who had not undergone esophageal surgery. Results: At the time of the study, 31 subjects were pH normal, 10 abnormal. Columnar biopsies were collected from 21 of the pH normal and 9 pH abnormal subjects, and all no surgery subjects. Complete regression of columnar mucosa was seen in 7 subjects with pH normal and 1 with pH abnormal. The length of Barrett esophagus did not differ between groups preoperatively, but was significantly less at the time of the study in the pH normal compared with pH abnormal or no surgery groups. Significantly, fewer genes were methylated in the pH normal than the pH abnormal or no surgery groups, which did not differ from each other. The number of methylated genes correlated with increased reflux, intestinal metaplasia, and increased columnar-lined esophagus length, but not acid-suppression medication. Conclusions: Fundoplication that reduces reflux to normal levels can lead to regression of the columnar mucosa. Reflux is associated with aberrant DNA methylation, and control of reflux reduces deleterious genomic changes associated with cancer.