Background: The treatment of children with attention deficit hyperactivity disorder (ADHD) and Tourette syndrome (TS) has been problematic because methylphenidate (MPH)-the most commonly used drug to treat ADHD-has been reported to worsen tics and because clonidine (CLON)-the most commonly prescribed alternative-has unproven efficacy. Methods: The authors conducted a multicenter, randomized, double-blind clinical trial in which 136 children with ADHD and a chronic tic disorder were randomly administered CLON alone, MPH alone, combined CLON + MPH, or placebo (2 × 2 factorial design). Each subject participated for 16 weeks (weeks 1-4 CLON/placebo dose titration, weeks 5-8 added MPH/placebo dose titration, weeks 9-16 maintenance therapy). Results: Thirty-seven children were administered MPH alone, 34 were administered CLON alone, 33 were administered CLON + MPH, and 32 were administered placebo. For our primary outcome measure of ADHD (Conners Abbreviated Symptom Questionnaire-Teacher), significant improvement occurred for subjects assigned to CLON (p < 0.002) and those assigned to MPH (p < 0.003). Compared with placebo, the greatest benefit occurred with combined CLON + MPH (p < 0.0001). CLON appeared to be most helpful for impulsivity and hyperactivity; MPH appeared to be most helpful for inattention. The proportion of individual subjects reporting a worsening of tics as an adverse effect was no higher in those treated with MPH (20%) than those being administered CLON alone (26%) or placebo (22%). Compared with placebo, measured tic severity lessened in all active treatment groups in the following order: CLON + MPH, CLON alone, MPH alone. Sedation was common with CLON treatment (28% reported moderate or severe sedation), but otherwise the drugs were tolerated well, including absence of any evident cardiac toxicity. Conclusions: Methylphenidate and clonidine (particularly in combination) are effective for ADHD in children with comorbid tics. Prior recommendations to avoid methylphenidate in these children because of concerns of worsening tics are unsupported by this trial.