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Autism spectrum disorders (ASDs) are neurodevelopmental disorders that comprise wide graduated clinical expressions but similar core symptoms (repetitive, stereotyped behavior, and social communication disabilities). Many patients with ASD have disruptive behaviors like aggressiveness, temper tantrums, or self-injury that interfere with their socializations, their learning abilities, and their quality of life. These behaviors represent a common target for pharmacology. Beherec et al (J Clin Psychopharmacol. 2011;31:341–344) (first cohort), showed the efficacy of clozapine on disruptive behaviors in 6 patients with autism who were older than 16 years. The aim of this study was to assess the efficacy and tolerance of clozapine in a new cohort and the long-term effect in our first cohort.Concerning the replication study, we conducted a retrospective study of the changes of aggressive behaviors for all patients with ASD who were treated with clozapine from 2011 to 2017. Disruptive behaviors were monitored from 1 to 6 months before and after the initiation of the clozapine.All the patients of the first cohort were still on clozapine after an average of 11 + 2.6 years, with the same efficacy and no serious adverse effect was noted. For the replication study, 13 patients were included. Clozapine resulted in a significant decrease in the number of the days with aggression (65.2% + 32.6%). Once again, no serious adverse effect was notified. All the patients had a better quality of life.Our study confirms that clozapine could be an efficacious and well-tolerated treatment for ASD patients with disruptive behaviors who do not respond to other antipsychotics on the long term.