Proton pump inhibitors (PPIs) are widely used in the management of gastroesophageal reflux. However, several studies have demonstrated serious adverse events associated with PPI use including cardiovascular disease, acute kidney injury, chronic kidney disease, dementia, pneumonia, gastric cancer, Clostridium difficile infection, and increased risk of fracture. Recent evidence has also suggested an increased risk of all-cause mortality. To estimate all-cause and cause-specific mortality with acid suppression, a longitudinal cohort study of 214,467 United States veterans newly using histamine H2 receptor antagonists (H2RAs) (n=157,625) or PPIs (n=56,842) between July 2002 and June 2004 was conducted. Department of Veterans Affairs databases were used to obtain data regarding demographic characteristics, encounters with the healthcare system (both inpatient and outpatient), comorbidities, procedures, surgeries, laboratory results, outpatient prescription records, and date and underlying cause of death. With a 10-year follow-up, 45.20 excess deaths per 1,000 patients taking PPIs were reported (95% CI 28.20 to 61.40). PPI use was also associated with increased circulatory system diseases (number of attributable deaths per 1000 patients 17.47, 95% CI 5.47 to 8.80), neoplasms (12.94, 95% CI 1.24 to 24.28), infectious and parasitic diseases (4.20, 95% CI 1.57 to 7.02) and genitourinary system diseases (6.25, 95% CI 3.22 to 9.24). Cumulative duration of PPI use was associated with increased all-cause mortality. The results of this study therefore suggest an increase in cardiovascular disease, chronic kidney disease and upper gastrointestinal cancer-related death with PPI use, warranting greater stewardship regarding PPI prescription and usage.