The purpose of this study was to characterize children with Down syndrome and attention-deficit hyperactivity disorder (ADHD) with disruptive behaviors using the Aberrant Behavior Checklist (ABC), and to measure the treatment effects of guanfacine on maladaptive behaviors. Subjects were enrolled from a group of outpatients who visited our clinic between 2002 and 2007. Subjects (N = 23) were children with Down syndrome ages 4 to 12 years (mean 7.4 ± 4.1), who met criteria for ADHD according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition The Aberrant Behavior Checklist Irritability and Hyperactivity subscales each showed a significant decrease (P < .0001) at follow-up. The mean decline on Hyperactivity was 25% (-7.8 points), and for Irritability, 25% (-3.5 points). The mean composite score also declined by 24% (-12 points). Effect size differences on Irritability were moderate, whereas differences on Hyperactivity and composite score appeared large. Clinically important target behaviors were reduced. Medication was generally well tolerated and the incidence of treatment emergent side effects remained low.