Objective: The relationships of attention deficit hyperactivity disorder (ADHD), conduct disorder, and gender to substance abuse were studied in a large population-based sample of adolescent twins. Method: Structured interviews were administered to 626 pairs of 17-year-old twins (674 girls and 578 boys) and their mothers to generate lifetime psychiatric diagnoses, and computerized measures of current substance use were obtained. Hierarchical logit analyses were performed to assess the independent effects of ADHD, conduct disorder, and gender on current substance use, frequency of substance use, and DSM-IIIR diagnoses of substance use disorders. Results: Conduct disorder was found to increase the risk of substance use and abuse in adolescents regardless of gender. In contrast, independent of its association with conduct disorder, an ADHD diagnosis did not significantly increase the risk of substance use problems. Conclusions: This study found no significant gender differences in the effects of ADHD and conduct disorder on substance use and abuse, although there was some suggestion that girls with ADHD might be at slightly higher risk than boys for substance abuse. In addition, increased risk of substance abuse among adolescents with conduct disorder may be primarily confined to those with persistent conduct disorder.