To examine the validity of oppositional defiant disorder (ODD) as a clinical phenotype distinct from attention-deficit hyperactivity disorder (ADHD), parents and teachers completed a DSM-IV-referenced rating scale and a background questionnaire for 608 children (ages 3–12 years) with autism spectrum disorder (ASD). The ASD sample was separated into four groups: ODD, ADHD, ODD + ADHD, and neither (NONE). Comparison samples were non-ASD clinic (n = 326) and community (n > 800) controls. In the ASD sample, all three ODD/ADHD groups were clearly differentiated from the NONE group, and the ODD + ADHD group had the most severe co-occurring symptoms, medication use, and environmental disadvantage. There were few differences between ASD + ODD and ASD + ADHD groups. Findings for ASD and control samples were similar, supporting overlapping mechanisms in the pathogenesis of ODD.