Background <p>There are conflicting results and potential methodological flaws of previous observational studies on the association between T2DM and the risk of gastric cancer.This two-sample Mendelian randomization (MR) study aimed to investigate the causal association between type 2 diabetes mellitus (T2DM) and gastric cancer in different ethnic populations.</p> Methods <p>Exposure variables were obtained from genome-wide association studies (GWAS) of T2DM in European population (finn-b-E4_DM2; 32,469) and East Asian population (ebi-a-GCST90018706; n = 45,383). Concomitantly, we utilized summary-level genetic data for gastric cancer in Europeans population (ebi-a-GCST90018849; n = 1029) and East Asians population (ebi-a-GCST90018629; n = 7,921) as the outcome measure. Causal associations between T2DM and gastric cancer in the same ethnic groups were primarily determined using the inverse-variance weighted (IVW) method.</p> Results <p>A total of 62 and 106 single nucleotide polymorphisms associated with T2DM were selected for in Europeans and East Asians, respectively. The IVW analysis indicated that there was a significant inverse association between T2DM and gastric cancer in Europeans (odds ratio [OR] 0.917; 95% confidence interval [CI] 0.855–0.984) and East Asians (OR 0.881; 95% CI 0.845–0.918). The weighted median and Weighted mode regression models produced similar results. MR-Egger regression analysis suggested the absence of horizontal pleiotropy. The leave-out sensitivity analysis demonstrated that the results were stable.</p> Conclusion <p>This MR study revealed that T2DM may be associated with a reduced risk of gastric cancer in European and East Asian population.</p>