The objective of the study was to systematically examine patterns of psychiatric comorbidity in referred youth with autism spectrum disorders (ASD) including autistic disorder and pervasive developmental disorder not otherwise specified. Consecutively referred children and adolescents to a pediatric psychopharmacology program were assessed with structured diagnostic interview and measures of psychosocial functioning. Comparisons were made between those youth satisfying diagnostic criteria for ASD and age and sex matched youth without ASD referred to the same clinical program. 9.3% (217/2323) of the referred youth (age range: 3–17 years) met DSM-III-R criteria for ASD. ASD youth suffered from significantly higher number of comorbid disorders than comparisons (6.4 ± 2.7 vs. 5.2 ± 2.9; p < 0.001). Ninety-five percent of the youth with ASD had three or more comorbid psychiatric disorders and 74% had five or more comorbid disorders. ASD youth were also more functionally impaired and required extra-assistance in school and therapeutic interventions at higher rates than age and sex matched non-ASD referred youth. Youth with ASD have high levels of psychiatric comorbidity and dysfunction comparable to the referred population of youth without ASD. These findings emphasize the heavy burden of psychiatric comorbidity afflicting youth with ASD and may be important targets for intervention.