The impact of antiplatelet drugs (APDs) on the rupture risk of unruptured intracranial aneurysms (uIAs) remains controversial. This study aimed to evaluate the causal effects of APDs on aneurysmal subarachnoid hemorrhage (aSAH) and uIA.A two-sample Mendelian randomization (TSMR) analysis examined associations between genetically proxied platelet reactivity and aSAH. The therapeutic inhibition of platelet aggregation by five widely used APDs was proxied by expression quantitative trait loci (eQTL) from eqtlGen consortium and GTEx v8 consortium and protein quantitative trait loci (pQTL) from deCODE database. Causal effects were estimated with summary-data-based Mendelian randomization (SMR), TSMR, colocalization analysis, and sensitivity analysis. Mediation MR analysis explored potential pathways.The platelet reactivity was inversely associated with the risk of aSAH, exhibiting no discernible heterogeneity or pleiotropic effects (odds ratio [OR], 0.883, 95% confidential interval, 0.833-0.936; p=2.67E-05). No causal effects on the aSAH and uIA were observed for the majority of antiplatelet drug target genes by SMR, TSMR, and colocalization analysis. However, elevated genetic expression of PEAR1 was associated with increased platelet reactivity with an OR of 1.46 (β1=0.375, se=0.072; p=1.99E-07), and this elevation showed significant inverse association with aSAH risks (β2=-0.125, se=0.030; p=2.67E-05).The platelet reactivity was inversely associated with aSAH risk. However, APDs were not identified as either risk or protective agents for aSAH or uIA. Targeting PEAR1 might reduce platelet reactivity and increase aSAH risk, highlighting the need for further research.Copyright © 2025. Published by Elsevier Inc.