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Objective: In this study, it was intended to explore the causal association between mean platelet volume (MPV) and risk of deep vein thrombosis (DVT) using a two-sample Mendelian randomization (MR) analysis and a retrospective study., Methods: This study applied two-sample MR analysis to estimate the causal association between MPV and risk of DVT. Twenty-one single nucleotide polymorphisms (SNPs) were selected as genetic variants from two independent consortiums cohorts (p-value <5×10 -8 , linkage disequilibrium r 2 <0.1). Inverse variance weighted (IVW), MR-egger method and weighted median were performed. A retrospective study was also conducted to verify the associations identified from the MR study., Results: The MR analysis demonstrated that genetically predicted higher MPV was associated with significantly lower risk of DVT (OR 0.982, 95% CI = 0.967-0.998, P = 0.023), with the consistent result in weighted median and MR-Egger. There was no directional horizontal pleiotropy in the method of MR-Egger regression (intercept=2.9e-04, P = 0.194). There was no single SNP was found to strongly drive the combined causal effect in the leave-one-out sensitivity analysis. Additionally, the similar result was observed in the retrospective study., Conclusion: This study suggested that MPV was negatively associated with the risk of DVT. More basic researches are needed in the future to explore its specific mechanism., Competing Interests: The authors report no conflicts of interest in this work., (© 2023 Li and Liang.)