Febrile seizures are the most common form of childhood seizures. Fever is induced by increased high mobility group box-1 (HMGB-1) level during infection and this may trigger the development of febrile seizures. HMGB1 is a highly conserved, ubiquitous protein present in the nuclei and cytoplasm of nearly all cell types. HMGB1 has been shown to be a key mediator of inflammatory diseases.HMGB1 was involved in the generation of febrile seizures. This work aimed to determine the role of HMGB1 as a proinflammatory cytokine in the pathogenesis of febrile seizures. Our study included 50 patients with febrile seizures. Control samples were collected from children with febrile illness without seizures n=51cases, afebrile seizures children (known epileptic) n=10 cases, and afebrile healthy n=25 children. Both patients and control groups were subjected to history taking, complete neurological examination, laboratory investigations (serum blood [sodium, potassium, calcium, blood urea nitrogen, creatinine], C-reactive protein, complete blood count and serum HMGB-1). Results Serum (HMGB-1) was significantly higher in patients with febrile seizures than other groups.In conclusion, From this study we conclude that HMGB1 were significantly higher in patients with febrile seizures. Our data suggest that HMGB1 may be contribute to the generation of febrile seizures in children.