Attention-deficit/hyperactivity disorder (ADHD) is a common child and adolescent disorder that is associated with negative outcomes (e.g., emotional and behavioral problems, substance use) and is often comorbid with Conduct Problems (CP). Research findings are mixed as to whether youth with ADHD alone or comorbid ADHD/CP suffer from low self-esteem. Research has also shown links between low self-esteem and ADHD (alone and with CP) with substance use; yet, no research has examined the links between self-esteem and substance use in adolescents with ADHD and CP. The current study examined the relation between ADHD with and without comorbid CP and self-esteem, and whether self-esteem moderated the relation between ADHD and ADHD/CP with substance use among adolescents. We hypothesized that adolescents with comorbid ADHD/CP would experience lower self-esteem than adolescents with ADHD alone or with neither disorder and that self-esteem would moderate the association between ADHD, CP, and substance use. Participants were 62 adolescents who completed the laboratory-based study with a parent. Results suggested that adolescents with comorbid ADHD and CP had significantly lower self-esteem than adolescents with ADHD alone or neither disorder. Self-esteem was not significantly different for adolescents with ADHD alone versus those in the control group. There was one marginally significant interaction between ADHD and self-esteem predicting substance use, such that individuals with comorbid ADHD/CP who also had low self-esteem tended to use more substances. Results have implications for treatments that target adolescents with ADHD and comorbid CP, as these adolescents are at risk for many deleterious outcomes.