Autistic children frequently exhibit irritability (aggression, self-injurious behavior, and severe tantrums), which leads to signi cant impairments. Two atypical antipsychotics have been licensed by the Food and Drug Administration for the treatment of irritability in autistic children, although a signi cant percentage of these children do not respond to this treatment. This study aimed to determine the frequency of drug refractory irritability (DRI) and identify the risk factors in a large clinical sample of autistic children. The medical records of 1279 children aged 2-18 years diagnosed with autism and undergoing clinical followup were retrospectively analyzed. Socioeconomic and clinical characteristics, co-occurring psychiatric disorders and physical conditions were recorded. Of the 1279 children, 8.2% met the DRI criteria. Older age, low maternal education, low family income, severe autism, language impairment, anxiety disorders, sleep di culties, GIS and dental problems were found to increase the risk of DRI. Our ndings indicate that a signi cant proportion of the clinical samples of autistic children had DRI. The physical, psychiatric, and environmental risk factors identi ed in our study also highlight heterogeneity in the etiology of DRI. Further research on DRI is needed to develop treatment and prevention strategies.