Purpose: We aimed to assess whether the aberrant methylation of GNAQ gene, which may involve in the clopidogrel resistance (CR), was associated with a higher risk of recurrent ischemic events in clopidogrel-treated acute ischemic stroke or transient ischemic attack (TIA) patients. Methods: This is a nested case-control study, 152 clopidogrel-treated acute ischemic stroke or TIA patients that were propensity-matched were included in the final analysis, including 36 patients with vascular recurrence set as cases. Methylation levels of GNAQ gene were identified with MassARRAY EpiTYPER assays. Univariate and multivariate logistic regression analyses were conducted to explore the predictive value of CpG units for recurrent ischemic events within 1 year.Mediation analysis was performed to assess the role of CR in describing the effect of GNAQ methylation on recurrent ischemic events. Results: A total of 16 differentially methylated CpG units were identified. Multivariate logistic analysis indicated that the average methylation of CpG 32-39 of GNAQ was associated with a significantly higher risk of ischemic events (p < 0.001). When transformed into dichotomous variables with the receiver operating characteristic curve, hypomethylation (<0.31) of CpG 32-39 of GNAQ significantly increased the risk of vascular recurrence (odds ratio 73.82, 95% confidence interval 20.33-268.01). The mediation effect of CR for recurrent ischemic events was not identified. Conclusions: Hypomethylation of CpG 32-39 of GANQ gene was associated with a higher risk of ischemic events for clopidogrel-treated acute ischemic stroke or TIA patients. Further studies were warranted to explain the possible mechanism.