PurposeThis study aims to determine the causal effect of chronic obstructive pulmonary disease (COPD) on different subtypes of lung cancer and to investigate the mediation effects of COPD between smoking and the subtypes of lung cancer.MethodsThe study utilized summary level data from genome-wide association studies. It extracted independent single nucleotide polymorphisms (SNP) to serve as instrumental variables (IV). We conducted two-sample MR analyses primarily using inverse-variance weighting, as well as MR-Egger and MR-PRESSO to establish and validate the causal impact of COPD on lung cancer subtypes. Additionally, multivariable MR analysis was employed to ascertain the mediating role of COPD between smoking and lung cancers.ResultsThe two-sample MR analysis demonstrated that COPD is linked to an elevated risk of lung adenocarcinoma (OR: 1.48, 95% CI 1.35-1.61, p = 0.009) and squamous cell carcinoma (OR: 1.78, 95% CI 1.62-1.93, p = 0.001). Further, using multivariable MR, it was established that COPD mediates the causal effects of smoking on lung adenocarcinoma by 56.52% (95% CI 17.51-95.52%) and 63.61% (95% CI 38.31-88.92%) in lung squamous cell carcinoma.ConclusionOur study found that COPD was a risk factor for developing both lung adenocarcinoma and squamous cell carcinoma. COPD also played a crucial role in mediating the causal effects of smoking on these two subtypes of lung cancer.