Purpose: To investigate the effect of proton pump Inhibitors (PPI) use in patients with gastro esophageal reflux disease (GERD) on the development of esophageal cancer in the US veteran population. Background: PPIs are commonly used medications for treating GERD, however clinical data for protection against esophageal malignant tumors in patients with GERD is lacking. Methods: The VISN 16 database contains clinical and demographic information on all veterans (>1.4 million patients) who were treated in the South Central VA Health Care Network. The data was queried from Oct 1998 to June 2004, using a retrospective case control design. Statistical analysis was performed using SAS software version 9.0 (Chicago, IL). Multiple logistic regression analysis was used with calculation of odds ratios and 95% confidence intervals. The data was adjusted for age, smoking, alcohol use and diabetes. Results: A total of 483,733 patients were evaluated. The mean age was 61.2 (SD ± 15.1) years and 91.7% were men. Of these 80,784 patients with GERD (ICD-9: 530.11, 530.81) were included in the study. 55,875 (69.2%) patients were using PPI. Esophageal cancer (ICD code of 150) occurred in 223 (0.3%) patients. Using multivariate analysis PPI users were less likely to develop esophageal cancer (Odds ratio 0.52; 95% CI 0.40–0.70, p < 0.0001). Covariates studied included age, race, gender, smoking, alcohol use, BMI, NSAID use, statin use, and diabetes. Discussion: Our data should be evaluated with caution, given the limitations of the population, the database and the fact that this is a case controlled study. Patients were placed in the PPI users group if they were using PPI prior to the diagnosis of esophageal cancer however the dose, duration and type of PPI used were not factored into the analysis. The pathological type of cancer is not available at this time. In addition, some factors known to increase the risk of esophageal cancer like Barretts esophagus was not incorporated into the study. Conclusions: Proton Pump Inhibitors are associated with a 48% reduced incidence of esophageal malignant tumors after controlling for age, race, gender, smoking, alcohol use, BMI, NSAID use, statin use, and diabetes.