AbstractObjectiveSelf‐limited infantile epilepsy (SeLIE) has distinctive clinical features, and thePRRT2gene is known to be a considerable genetic cause. There have been a few studies onPRRT2‐positive SeLIE only, and anti‐seizure medications are often required due to frequent seizures at initial seizure onset. This study aimed to provide clinical information for the early recognition of patients withPRRT2‐positive SeLIE and to propose effective anti‐seizure medications for seizure control.MethodsWe retrospectively reviewed 36 patients diagnosed with SeLIE with genetically confirmed pathogenic variants ofPRRT2. In addition, six atypical cases with neonatal‐onset seizures and unremitting after 3 years of age were included to understand the expanded clinical spectrum ofPRRT2‐related epilepsy. We analyzed the initial presentation, clinical course, and seizure control response to anti‐seizure medications.ResultsPatients withPRRT2‐related epilepsy had characteristic seizure semiology at the initial presentation, including all afebrile, clustered (n = 23, 63.9%), short‐duration (n = 33, 91.7%), and bilateral tonic–clonic seizures (n = 26, 72.2%). Genetic analysis revealed that c. 649dupC was the most common variant, and six patients had a 16p11.2 microdeletion containing thePRRT2gene. One‐third of the patients were sporadic cases without a family history of epilepsy or paroxysmal movement disorders. In the 33 patients treated with anti‐seizure medications, sodium channel blockers, such as carbamazepine, were the most effective in seizure control.SignificanceOur results delineated the clinical characteristics ofPRRT2‐positive SeLIE, differentiating it from other genetic infantile epilepsies and discovered the effective anti‐seizure medications for initial clustered seizure control. If afebrile bilateral tonic–clonic seizures develop in a normally developed infant as a clustered pattern,PRRT2‐positive SeLIE should be considered as a possible diagnosis, and sodium channel blockers should be administered as the first medication for seizure control.