BACKGROUND: Helicobacter pylori (H. pylori) causes chronic infection in more than half of the population worldwide. Accumulating body of evidence indicates the possible role of H. Pylori infection in extra-intestinal health problems, including epilepsy. This study aims to investigate the efficacy of treating H. pylori infection on seizure frequency among children with drug-resistant idiopathic generalized epilepsy (IGE). METHODS: A parallel, two-arm, open-label, randomized controlled trial was conducted on 126 children with drug-resistant IGE and positive H. pylori stool antigen test who were randomly assigned to study and comparison groups in 1.2:1 ratio. Only the study group received H. pylori eradication therapy (esomeprazole, amoxicillin, and clarithromycin) for two weeks. The primary outcome was seizure improvement (≥ 50% seizure frequency reduction compared with baseline) after 2.5 months. Secondary outcomes were occurrence of status epilepticus, escalation of antiseizure medication (ASMs), and adverse effects. Outcomes between the two groups were compared using Chi-square/Fisher exact tests on an intention-to-treat principle. Logistic regression analysis was performed to investigate possible effects of baseline variables on primary outcome. RESULTS: Seizure improvement occurred in 23 (33%) children in the study group compared with seven (12%) children in the comparison group (Risk ratio [RR] 2.7, 95% confidence interval [CI]: 1.3-5.9; p 0.006). The study group had lower occurrence of status epilepticus (2.9% vs. 14%; RR 0.21, 95%CI: 0.05-0.93; p 0.042) and lesser need for ASMs escalation (4.4% vs. 19.3%; RR 0.23, 95%CI: 0.07-0.77; p 0.010). Adverse effects were more frequent among subjects in the study group, including nausea (15.9% vs. 10.5%) vomiting (8.7% vs. 3.5%), diarrhea (11.6% vs. 5.3%), and skin rash (4.4% vs. 1.8%), but the differences were not statistically significant (p > 0.05). None of baseline participants' variables was significantly associated with the primary outcome. CONCLUSION: Treating H. pylori infection may improve seizure control in children with drug-resistant IGE, but further studies are warranted to confirm our findings and explore mechanisms behind seizure improvement following H. pylori eradication therapy. TRIAL REGISTRATION: Registered on www. CLINICALTRIALS: gov (identifier: NCT05297695) on 17 March 2022. https://clinicaltrials.gov/study/NCT05297695 .