This article investigates the relationship between attention-deficit/hyperactivity disorder (ADHD) and psychoactive substance use disorders (PSUD) in siblings of ADHD and normal-control probands and addresses issues of psychiatric comorbidity and gender. Using DSM-III-R structured diagnostic interviews and blind raters, the authors conducted a 4-year follow-up of siblings. ADHD and male gender predicted higher rates and an earlier onset of PSUD after adjusting for high-risk status, other psychiatric disorders, and age. Risk was particularly high if the siblings had ADHD plus conduct disorder. This study's findings confirms the authors' prior report high-lighting the importance of drug and alcohol prevention and cessation programs aimed at ADHD youth and their siblings, particularly those with comorbid conduct disorder.