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Mozart's sonata for two pianos in D major, K448, has been shown to decrease interictal EEG discharges and recurrence of clinical seizures in both adults and young patients. In this prospective, open-label study, we evaluated the effect of listening to a set of Mozart's compositions, according to the Tomatis method, on sleep quality and behavioral disorders, including auto-/hetero-aggression, irritability, and hyperactivity, in a group of children and adolescents with drug-resistant epilepsy. The study group was composed of 11 outpatients (7 males and 4 females), between 1.5 years and 21 years of age (mean age: 11.9 years), all suffering from drug-resistant epileptic encephalopathy (n = 11). All of them had a severe/profound intellectual disability associated with cerebral palsy. During the study period, each patient had to listen to a set of Mozart's compositions 2 h per day for fifteen days for a total of 30 h, which could be distributed over the day depending on the habits and compliance of each patient. The music was filtered by a device preferably delivering higher sound frequencies (> 3000 Hz) according to the Tomatis principles. The antiepileptic drug therapy remained unchanged throughout the study period. During the 15-day music therapy, 2 out of 11 patients had a reduction of 50–75% in seizure recurrence, and 3 out of 12 patients had a reduction of 75–89%. Overall, 5 (45.4%) out of 11 patients had a ≥ 50% reduction in the total number of seizures, while the percentage decrease of the total seizure number (11/11) compared with baseline was − 51.5% during the 15-day music therapy and − 20.7% in the two weeks after the end of treatment. All responders also had an improvement in nighttime sleep and daytime behavior. [ABSTRACT FROM AUTHOR]