Objective: To evaluate the effect of atomoxetine hydrochloride versus placebo on attention-deficit/hyperactivity disorder (ADHD) and substance use disorder (SUD) in adolescents receiving motivational interviewing/cognitive behavioral therapy (MI/CBT) for SUD. Method: This single-site, randomized, controlled trial was conducted between December 2005 and February 2008. Seventy adolescents (13 through 19 years of age) with Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) (DSM-IV) ADHD, a DSM-IV ADHD checklist score greater than or equal to 22, and at least one nontobacco SUD were recruited from the community. All subjects received 12 weeks of atomoxetine hydrochloride + MI/CBT versus placebo + MI/CBT. The main outcome measure for ADHD was self-report DSM-IV ADHD checklist score. For SUD, the main outcome was self-report number of days used nontobacco substances in the past 28 days using the Timeline Followback interview. Results: Change in ADHD scores did not differ between atomoxetine + MI/CBT and placebo + MI/CBT (F4,191 = 1.23, p = 0.2975). Change in days used nonnicotine substances in the last 28 days did not differ between groups (F3,100 = 2.06, p = 0.1103). Conclusions: There was no significant difference between the atomoxetine + MI/CBT and placebo + MI/CBT groups in ADHD or substance use change. The MI/CBT and/or a placebo effect may have contributed to a large treatment response in the placebo group. (Contains 3 figures and 2 tables.)