PROJECT SUMMARY Children with Down syndrome (DS) have a 3-5 times greater prevalence of Attention Deficit Hyperactivity Disorder (ADHD) than typically developing children. Despite their higher risk of ADHD and consensus guideline recommendations to treat children with intellectual disability (ID) and comorbid ADHD with stimulants (the most efficacious ADHD treatment), children with DS+ADHD have disproportionately low rates of stimulant medication treatment. Possible reasons for under-utilization of stimulant treatment in DS+ADHD include: 1) diagnostic uncertainty regarding how to accurately diagnose ADHD in children with DS, making providers prone to “diagnostic overshadowing” (i.e., attributing ADHD to their ID); 2) the absence of any prior clinical trials examining the safety and efficacy of stimulant medication in children with DS+ADHD; and 3) concerns about cardiac safety, given the high incidence of congenital heart disease or defects (CHD) in the DS population. Based on R61 pilot trial findings, we propose the first randomized clinical trial of stimulant medication in children with DS+ADHD to provide evidence regarding the short and long-term safety and efficacy of stimulant use in children with DS+ADHD, both with and without CHD. One hundred (100) children with DS+ADHD aged 6-17 years will participate. Children with DS+ADHD will complete a multi-phased randomized, double-blind clinical trial with crossover to placebo and long-term follow-up to assess the short- and long-term efficacy and safety of stimulant medications for treating ADHD symptoms and impairment in children with DS. Study aims of the R33 will focus on 1) Assessing the short- and long-term safety of stimulant treatment in children with DS+ADHD with a specific focus on cardiac safety; 2) Determining the short- and long-term efficacy of stimulant treatment at remediating cognitive, behavioral, and functional impairments in children with DS+ADHD; and 3) Exploring moderators (e.g., IQ, ADHD subtype/presentation, executive functioning levels, comorbid internalizing disorders, CHD) of stimulant response and adverse effects. Results from this study will provide much needed diagnostic and treatment data that will directly impact the outcomes of the approximately 45,000 children with DS+ADHD nationwide.