Background: The mechanisms leading to lung fibrosis are still under investigation. Thisstudy aimed to demonstrate whether antacids could prevent the development of interstitiallung disease (ILD). Methods: This population-based longitudinal cohort study was conducted betweenJanuary 2006 and December 2010 in South Korea. Eligible subjects were ≥40 years ofage, exposed to proton pump inhibitors (PPI)±histamine-2 receptor antagonists (H-2blockers) or H-2 blockers only, and had no history of ILD between 2004 and 2005. Exposure to antacids was defined as the administration of either PPI or H-2 receptorantagonists for >14 days, whereas underexposure was defined as antacid treatmentadministered for less than 14 days. Newly developed ILDs, including idiopathic pulmonaryfibrosis (IPF), were counted during the 5-year observation period. The associationbetween antacid exposure and ILD development was evaluated using adjusted Coxregression models with variables, such as age, sex, smoking history, and comorbidities. Results: The incidence rates of ILD with/without antacid use were 43.2 and33.8/100,000 person-years, respectively and those of IPF were 14.9 and 22.9/100,000person-years, respectively. In multivariable analysis, exposure to antacid before the diagnosisof ILD was independently associated with a reduced development of ILD (hazardratio [HR], 0.57; 95% confidence interval [CI], 0.45 to 0.71; p<0.001), while antacidexposure was not associated with development of IPF (HR, 0.88; 95% CI, 0.72 to 1.09;p=0.06). Conclusion: Antacid exposure may be independently associated with a decreased riskof ILD development.