Abstract: Objective To investigate the association between proprotein convertase subtilisin/kexin type 9(PCSK9) gene polymorphism and the efficacy of tirofiban in intravascular treatment of acute ischemic stroke (AIS) patients. Methods A total of 180 AIS patients who were treated in Xuzhou Central Hospital between December 2023 and December 2024 were selected as a study group. Meanwhile, 180 healthy individuals were selected as a control group. The PCSK9 gene polymorphisms were tested in both groups. Logistic regression analysis was conducted to examine the association between PCSK9 genotypes and AIS occurrence. The effect of different rs562556 genotypes on coagulation-fibrinolysis indicators in AIS patients treated with eptifibatide were compared. Results Significant differences in genotype and allele distribution were found at the PCSK9 gene loci rs562556, rs2479408, and rs529787 between the two groups. The frequencies of alleles A and C at these loci were higher in the study group than in the control group (P<0.05). Multivariate logistic regression analysis showed that rs562556 gene polymorphism was an independent factor influencing AIS, with the AG+AA genotypes at rs562556 increasing the risk of AIS (P<0.05). After treatment, patients with the GG genotype had lower platelet adhesion rate (PAd), platelet aggregation rate (PAg), fibrinogen (FIB), and D-dimer (D-D) levels than those with the AG+AA genotypes (P<0.05). Before treatment, GG genotype patients had higher PCSK9 levels than those with the AG+AA genotypes (P<0.05). After treatment, PCSK9 levels increased in both GG and AG+AA genotype patients, but PCSK9 levels in GG genotype patients were lower than those in AG+AA genotype patients (P<0.05). Conclusions The AG+AA genotypes at the rs562556 locus of the PCSK9 gene may increase the risk of AIS and are associated with the antiplatelet effect of tirofiban.