SummaryPurpose:  Febrile seizures (FS) are the most common form of childhood convulsions. Many reports have shown that a proinflammatory cytokine, interleukin‐1 (IL‐1) β, may have a facilitatory effect on the development of FS. We have previously shown that the IL1B ‐511C/T single nucleotide polymorphism (SNP) is associated with simple FS of sporadic occurrence. The balance between pro‐ and antiinflammatory cytokines influences the regulation of infections and could, therefore, play a role in the pathogenesis of FS. Here, to determine whether pro‐ and antiinflammatory cytokine genes are responsible for the susceptibility to FS, we have performed an association study on functional SNPs of cytokine genes in FS patients and controls.Methods:  The promoter SNPs of four inflammatory cytokine genes (IL6 ‐572C/G, IL8 ‐251A/T, IL10 ‐592A/C and TNFA ‐1037C/T) were examined in 249 patients with FS (186 simple and 63 complex FS) and 225 controls. Because the IL10 ‐592 SNP showed a positive association with FS, two additional SNPs (IL10 ‐1082A/G and ‐819T/C) were subjected to haplotype analysis. Furthermore, we examined the in vivo role of IL‐10 in hyperthermia‐induced seizures using immature animal models.Results:  The frequencies of the IL10 ‐592C allele and ‐1082A/‐819C/‐592C haplotype were significantly decreased in FS as compared with in controls (p = 0.014 and 0.013, respectively). The seizure threshold temperature in the IL‐10–administered rats was significantly higher than that in the saline‐treated control ones (p = 0.027).Conclusions:  The present study suggests that IL‐10 is genetically associated with FS and, contrary to IL‐1β, confers resistance to FS.