OBJECTIVE: The authors evaluated the association between attention deficit hyperactivity disorder (ADHD) and psychoactive substance use disorders in adults with ADHD, attending to comorbidity with mood, anxiety, and antisocial disorders. It was hypothesized that psychiatric comorbidity would be a risk factor for psychoactive substance use disorders. METHOD: Findings for 120 referred adults with a clinical diagnosis of childhood-onset ADHD were compared with those for non-ADHD adult comparison subjects (N = 268). All childhood and adult diagnoses were obtained by structured psychiatric interviews for DSM-III-R. RESULTS: There was a significantly higher lifetime risk for psychoactive substance use disorders in the ADHD adults than in the comparison subjects (52% versus 27%). Although the two groups did not differ in the rate of alcohol use disorders, the ADHD adults had significantly higher rates of drug and drug plus alcohol use disorders than the comparison subjects. ADHD significantly increased the risk for substance use disorders independently of psychiatric comorbidity. Antisocial disorders significantly increased the risk for substance use disorders independently of ADHD status. Mood and anxiety disorders increased the risk for substance use disorders in both the ADHD and comparison subjects, but more demonstrably in the comparison subjects. CONCLUSIONS: Although psychiatric comorbidity increased the risk for psychoactive substance use disorders in adults with ADHD, by itself ADHD was a significant risk factor for substance use disorders. More information is needed to further delineate risk and protective factors mediating the development of substance use disorders in persons with ADHD.