To investigate the clinical value of cytological gamma-glutamyl transpeptidase (gamma-GT) staining in the reduction of the morbidity and mortality of esophageal cancer in an area of China that has a high incidence of esophageal cancer. The results of pathology, cytological examination with gamma-GT staining in 451 patients with severe dysplasia were analyzed and followed-up for 3 years. At the 1-year follow-up, 17 of 231 patients with positive gamma-GT staining (7.4%) had developed esophageal cancer, but no cancer was detected in 95 patients with negative gamma-GT staining. Among 215 patients who were followed-up for 3 years, the risk of developing cancer in gamma-GT staining positive patients with grade I or II severe dysplasia was 5.7% and 14.3%, respectively. However, esophageal cancer was not found in patients with negative gamma-GT staining or in patients with positive gamma-GT staining who were younger than 40 years. These findings suggest that gamma-GT staining can be used as a cancer risk marker of esophageal epithelial dysplasia. Esophageal dysplasia needs to be further categorized according to gamma-GT staining for esophageal cancer prevention, and intervention is required for gamma-GT staining positive patients with severe dysplasia in order to increase the cost-benefit ratio of esophageal cancer prevention.