This review evaluates the current knowledge about the recognition of histologic esophageal mucosal changes in patients with nonerosive gastroesophageal reflux disease and analyzes the technical factors relevant to their interpretation. Studies investigating histologic changes in individuals with nonerosive reflux disease were identified by systematic Medline/PubMed searches from January 1966 to October 2005. Dilation of intercellular spaces was the most consistently reported histologic change in the esophageal mucosa of patients with nonerosive reflux disease, being observed in 41%-100% of patients and 0%-30% of controls. The mean intercellular space width was at least 2 times greater in patients than in controls, irrespective of esophageal acid exposure. Basal cell hyperplasia was observed in 9%-90% of patients compared with 10%-55% of controls. Papillary elongation was observed in 0%-85% of patients and 5%-20% of controls. Both of these features were more prevalent in reflux disease patients with abnormal esophageal acid exposure. All histologic changes responded to acid-suppressive therapy. Inflammatory cell infiltration was seldom observed or had a similar prevalence in patients and controls. Disparities in reported frequencies of change among studies were most likely caused by methodologic factors, most importantly the use of different methods for identifying patients and controls, for histologic sampling, and for biopsy scoring. The reviewed studies suggest that at least two thirds of patients with nonerosive reflux disease have histologic evidence of esophageal injury. Additional work is needed to assess the potential of these histologic changes for the diagnosis and assessment of reflux disease.