Purpose <p>No psychotropic treatment has recognized effects on the core clinical signs of autism. In this retrospective study, we sought to identify predictors of psychotropic medication in autistic adults among demographic, diagnostic and functional clinical factors.</p> Methods <p>A total of 391 records of adults (28.2 ± 9.6 years) from the Centre de Ressources Autisme Centre Val de Loire were included. Participants were divided into three groups: those with Autism Spectrum Disorder (ASD) (<i>n</i> = 129), those with Intellectual and Developmental Disabilities (IDD) (<i>n</i> = 48), and those with both diagnoses (ASD + IDD) (<i>n</i> = 214). Multinomial logistic regression analyses were performed to assess factors associated with psychotropic pharmacotherapy in autistic adults.</p> Results <p>17% of autistic adults without IDD and 44.9% of autistic adults with IDD were prescribed multiple psychotropic medications. The first regression analysis showed that the likelihood of psychotropic polypharmacotherapy increases with age, epilepsy and severe externalizing behavior disorders. Anxiety disorders were associated with psychotropic monopharmacotherapy and mood disorders were a significant predictor to both mono and polypharmacotherapy. The second regression analysis highlighted that IDD is an explanatory factor for psychotropic polypharmacotherapy and ASD + IDD is predictive for both mono and polypharmacotherapy. Adults with ASD + IDD are prescribed more psychotropic medication than those with ASD alone, particularly antiepileptics, benzodiazepines and neuroleptics.</p> Conclusion <p>Our study shows that co-occurring IDD, older age, epilepsy, anxiety and mood disorders, and externalizing behavioral disorders predict psychotropic medication use in autistic adults. The prevalence and the predictors of polymedication in this group raise concerns, emphasizing the need to develop new psychoeducational support and advance more targeted and effective treatments.</p>