INTRODUCTION: Lung cancer is a leading cause of mortality in the USA. Non-small cell lung cancer (NSCLC) contributes to 85% of all lung cancers. It is the most prevalent subtype amongst non-smokers and its incidence has risen in the last 20 years. Gastroesophageal reflux disease (GERD) has been reported to be associated with several lung pathologies, namely idiopathic pulmonary fibrosis, and asthma. We aimed to investigate the association between GERD and NSCLC by performing a retrospective, multicentered, case-control study. This is the first study of this nature to be carried out in the USA. METHODS: Data was retrieved from 17 Northwell health care facilities in the New York area between years, 2010–2018. Inclusion criteria were patients >18 years of age with NSCLC (large cell, adenocarcinoma, and squamous cell) and were appropriately matched with controls based on age, gender, weight, co-morbidities, and medication use. Our exposure group had a diagnosis of GERD based on ICD-9/10 codes, endoscopic, and/or histological evidence. We excluded patients with secondary lung cancers, esophageal adenocarcinoma, or other primary malignancies, Barrett’s esophagus, as well as smokers. Statistical analysis was carried out using SAS (SAS Institute, NC, USA). Logistic regression was conducted to determine the adjusted odds ratio (OR) and corresponding 95% confidence interval (CI) for the association between NSCLC and GERD. RESULTS: A total of 1,083 subjects were included in our study: 543 (50%) patients were diagnosed with NSCLC. In this population, GERD was twice as prevalent when compared to controls (20.4% vs. 11.6%, P < 0.001). Multivariate analysis demonstrated that GERD was associated with a higher risk of NSCLC compared to matched controls (OR = 1.86, 95% CI = 1.26–2.73). GERD patients treated with either antihistamines or proton pump inhibitors did not demonstrate an overall reduced risk of NSCLC (OR = 1.01, 95% CI = 0.48–2.12). Other independent risk predictors of NSCLC are summarized in Table 2. CONCLUSION: Our study demonstrates that GERD might be associated with a higher risk NSCLC, irrespective of the treatment of GERD. We postulate that GERD patients may suffer from chronic micro-aspirations leading to a prolonged inflammatory state within the lung parenchyma triggering proliferative signaling pathways leading to malignant transformation. Prospective trials are needed to further explore this relationship and clarify the role of GERD therapy.Table 1.: Baseline demographic characteristics of patients with Non-small cell lung cancer (NSCLC) and controlsTable 2.: Multivariate logistic regression analysis for the risk predictors of Non-small cell lung cancerFigure 1.: Forest plot of odds ratio (OR) values according to the independent risk predictors of non-small cell lung cancer.