BACKGROUND Epilepsy is one of the most common neurological diseases with unclear etiology where its genetic background and treatment regime still need further exploration. OBJECTIVE This study designed to evaluate the pharmacogenomics of MTHFR and ABCC2 genes, and their association with epilepsy susceptibility among Jordanian population. METHODS A case-control study was conducted on Jordanian cohort of 296 epileptic patients and 299 healthy individuals. Custom platform array was used to genotype the genetic polymorphisms within MTHFR (rs1801133) and ABCC2 (rs717620, rs3740066, rs2273697) genes. RESULTS This study revealed a significant genetic association of MTHFR rs1801133 polymorphism with susceptibility to generalized in general and generalized tonic-clonic epilepsy (GTCE)(p=0.018 and 0.01, respectively). Regarding ABCC2 gene, rs717620 was of linkage with generalized and GTCE subtypes (p=0.045 and 0.048, respectively), while rs717620 was associated with poor responder patients (p=0.036) with no linkage of the ABCC2 haplotypes. CONCLUSIONS MTHFR and ABCC2 polymorphisms showed an association with either epilepsy types in general or subtypes and treatment response among Jordanian population. This study also suggested that these gene polymorphisms have an important role in epilepsy development and drug effectiveness and could be of a great impact in the era of epilepsy diagnosis and treatment.