Observational studies have suggested a positive association between gastroesophageal reflux disease and lung cancer, but due to the existence of confounders, it remains undetermined whether gastroesophageal reflux disease (GERD) has a causal association with lung cancer. Therefore, Mendelian randomization (MR) analyses were applied to investigate the relationship between the two conditions. Two-sample Mendelian randomization analysis was utilized with summary genetic data from the European Bioinformatics Institute (602,604 individuals) and International Lung Cancer Consortium, which provides information on lung cancer and its histological subgroups. Furthermore, we used two-step Mendelian randomization and multivariable Mendelian randomization to estimate whether smoking initiation (311,629 cases and 321,173 controls) and alcohol intake frequency (n = 462,346) mediate any effect of gastroesophageal reflux disease on lung cancer risk. The Mendelian randomization analyses indicated that gastroesophageal reflux disease was associated with and significantly increased the risk of lung cancer (ORIVW = 1.35, 95% CI = 1.18-1.54; p = 1.36 × 10-5). Smoking initiation and alcohol intake frequency mediated 35% and 3% of the total effect of gastroesophageal reflux disease on lung cancer, respectively. The combined effect of these two factors accounted for 60% of the total effect. In conclusion, gastroesophageal reflux disease is associated with an increased risk of lung cancer, and interventions to reduce smoking and alcohol intake may reduce the incidence of lung cancer.Copyright © 2023 Yang, Nie, Chen, Liu, Li, Gong and Liu.