Objectives: Autistic children frequently exhibit irritability, which can manifest as aggression, self-injurious behaviour, and severe tantrums, leading to significant impairments. Two atypical antipsychotics have been licensed by the Food and Drug Administration for the treatment of irritability in autistic children, although a significant 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. Methods: The medical records of 1279 children aged 2-18 years diagnosed with autism and undergoing clinical follow-up were retrospectively analysed. Socioeconomic and clinical characteristics, co-occurring psychiatric disorders and physical conditions were recorded. Results: 55% of the sample used antipsychotics to treat irritability, and 8.2% met the DRI criteria. Older age, severe support requirement for autism, language impairment, anxiety disorders, sleep difficulties, gastrointestinal system, and dental problems were found to significantly increase the risk of DRI. Conclusion: Our findings indicate that a significant proportion of the clinical sample of autistic children had DRI. The physical, psychiatric, and environmental risk factors identified in our study also highlight heterogeneity in the etiology of DRI. Further research on DRI is needed to develop treatment and prevention strategies.