Epilepsy still causes the most burden compared to any other neurological diseases in children. Recent studies point to a connection between inflammation and epilepsy, particularly in epileptogenic epilepsy development, and the long-term effects of seizures. This pilot study describes the increasing serum High Mobility Group Box 1 (HMGB1) in two children with treatment-resistant epilepsy and how this marker could be considered a promising biomarker for treatment-resistant epilepsy in children. Case 1: A four-year-eight-month-old boy was presented with treatment-resistant epilepsy, communicating hydrocephalus on the ventriculoperitoneal shunt, cerebral palsy and global developmental delay. The seizure form was involuntary jerky head twisting and body shivering three times a day. Despite three antiepileptic medications (valproic acid, phenobarbital, and levetiracetam) given in maximal dose, the seizures were not well-controlled, three up to four times per week. The serum HMGB1 level was 5.93 ng/ml. Case 2: A four-year-three-month-old boy was presented with treatment-resistant epilepsy, cerebral palsy, global developmental delay, and sensorineural hearing loss. His first seizure started as status epilepticus. Symptoms progressed to generalized tonic seizures, with eyes bulging upward, occurring more than five times a day. The patient still suffers seizures daily for one minute despite the maximal dosage of valproic acid and levetiracetam therapy. The serum HMGB1 level was 5.342 ng/ml. Serum HMGB1 could be considered a potential biomarker for treatment-resistant epilepsy in children. Further diagnostic studies with adequate sample sizes are needed to support the proposed aetiology for developing targeted treatment options.