Methylation of MTHFR significantly increases susceptibility risk for ischemic stroke but does not affect ischemic stroke severity. MTHFR CpG A outperforms CpG B in mediating folate and vitamin B12 levels to increase ischemic stroke susceptibility by 4.73-fold; however, neither CpG was correlated with serum homocysteine levels. Here, MTHFR is linked to ischemic stroke.