Abstract Background: Febrile seizures are the most common form of childhood seizures. Among pro-inflammatory cytokines, interleukin-6 is the key acute-phase cytokine. To date, only a few studies concerned the association of interleukin-6 gene polymorphisms with febrile seizures.In this study, we aimed to investigate 3 cytokine singlenucleotide polymorphisms situated at positions –174 (G/C), –572 (G/C), and –597 (G/A) in the promoter region of the interleukin-6 gene for the first time in Egyptian children with febrile seizures. Methods: This was a case–control study included 100 patients with febrile seizure, and matched with age, gender, ethnicity 100 healthy control subjects. Interleukin-6 –174 (G/C), −572 (G/C), and −597 (G/A) polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), while the serum IL6 levels were measured by ELISA method. Results: Compared to the controls subjects, the frequency of the −174 GG and −597 GG IL6 genotypes were observed to be increased in children with febrile seizures (OR: 4.17; 95 % CI: 1.86–9.49; P <0.01 and OR: 1.96; 95 % CI: 1.06–3.63;P <0.05, respectively). We found a significant positive association between the −597 GG genotype and susceptibility to complex febrile seizures as did the G allele at the same position (OR: 4.2; 95 % CI: 1.4–13.3 for the GG genotype; P <0.01) and (OR: 2.89; 95 % CI: 1.1–7.7 for the G allele; P <0.05 respectively). Our data revealed no association between IL6- genotypes and serum IL6 levels in patients with febrile seizures (P > 0.05). Conclusion: In conclusion, our data brought a novel observation that the presence of a G allele or GG genotype at the −174 and the GG genotype at the −597 positions of the promoter region of the interleukin-6 gene constitute risk factors for developing febrile seizures in Egyptian children. Moreover, we observed a significant positive association between the IL6 –597 GG genotype and susceptibility to complex febrile seizures as did the G allele at the same position. However, we found no association between IL6- genotypes and serum IL6 levels in patients with febrile seizures