Objective To explore the association between two single nucleotide polymorphisms (SNP), rs1053005 and rs744166, in signal transducer and activator of transcription 3 (STAT3) gene and their susceptibility to childhood epilepsy. Methods A case control study was performed, in which 462 children with epilepsy including 121 children with intractable epilepsy were recruited. 493 healthy children were include as control group. PCR-RFLP was performed to investigate the two SNPs’ polymorphism. The relationship between the risk of children epilepsy and different genotypes and allelic genes was compared. Results Statistical differences of SNP rs1053005 genotype frequencies (AA, AG, GG) were found in epilepsy children as compared with control group ( χ2 =9.705, P =0.008). While the frequency of G allele in epilepsy children was obviously lower than that in the control group (OR =0.734, P =0.002, 95%CI: 0.604-0.892). There was no significant differences of SNP rs744166 genotype frequencies and C allele frequencies between epilepsy children and controls (P??＞??0.05). Conclusion SNP rs1053005 of STAT3 gene was associated with the risk of childhood epilepsy.