Introduction The aim of this study is to investigate the role of genetic variation and DNA methylation of PEAR1 rs12041331 in high on-treatment platelet reactivity (HPR) and recurrent ischemic stroke (RIS). Material and methods Genotype, methylation, and mRNA of PEAR1 rs12041331 were detected in patients with cerebral ischemia, for the analysis of the effect of PEAR1 rs12041331 on HPR and RIS. Results The major G allele of PEAR1 rs12041331 was associated with hypermethylation, which was associated with HPR. This link was not observed for RIS. Conclusions The PEAR1 rs12041331 genetic polymorphism and DNA methylation may be among the genetic factors affecting HPR. The correlation between PEAR1 and RIS needs to be studied further.