IMPORTANCE: Transcranial direct current stimulation (tDCS) has the potential to be a sustainable treatment option in pediatric attention-deficit/hyperactivity disorder (ADHD), but rigorously controlled multicenter clinical trials using state-of-the-art stimulation techniques are lacking. OBJECTIVES: To determine effect sizes of changes in cognitive and clinical measures and to assess safety and tolerability in the course of optimized multichannel tDCS over prefrontal target regions in pediatric ADHD. DESIGN, SETTING, AND PARTICIPANTS: In the sham-controlled, double-blind, parallel-group randomized clinical trial E-StimADHD (Improving Neuropsychological Functions and Clinical Course in Children and Adolescents With ADHD With Anodal Transcranial Direct Current Stimulation of the Prefrontal Cortex: A Randomized, Double-Blind, Sham-Controlled, Parallel Group Trial Using an Uncertified Class IIa Device) with 2 independent study arms, participants were enrolled from September 15, 2018, to August 10, 2021, and follow-up was completed October 4, 2021. Data were analyzed January 26, 2022, to November 8, 2023. The trial was conducted at the departments of child and adolescent psychiatry or pediatrics of 5 university hospitals in Portugal and Germany. Youths 10 to 18 years of age with ADHD according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (all presentations), an IQ of at least 80, and the ability to refrain from stimulant medication during participation in the trial were eligible. INTERVENTIONS: Optimized multichannel anodal tDCS or sham stimulation (1 mA, 20 minutes) targeting the left dorsolateral prefrontal cortex (lDLPFC; study A) or the right inferior frontal gyrus (rIFG; study B) was applied in 10 sessions, concurrent with performance on a cognitive target task (study A, working memory assessed in the n-back task; study B, interference control assessed in the flanker task). MAIN OUTCOMES AND MEASURES: Effect sizes for changes in accuracy measures (d-prime or flanker effect) in the target tasks assessed after the intervention. Primary analyses were based on the modified intention-to-treat set. RESULTS: This study included 69 youths (54 [78%] male) with a median age of 13.3 years (IQR, 11.9-14.9 years). Compared with sham tDCS, verum stimulation of the lDLPFC led to significantly lower working memory accuracy (effect size, -0.43 [95% CI, -0.68 to -0.17]; P = .001). Stimulation of the rIFG significantly improved interference control (effect size, 0.30 [95% CI, 0.04-0.56]; P = .02). Adverse events were mostly mild and transient and did not occur more often in the verum group. For example, the most frequent adverse events were headache (sham, n = 30; verum, n = 20), nasopharyngitis (sham, n = 11; verum, n = 5), and feeling of electric discharge (sham, n = 5; verum, n = 3). CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, prefrontal anodal tDCS induced small- to medium-sized effects in youths with ADHD, with only mild and transient adverse events. The optimized multichannel montage chosen to target the lDLPFC, however, decreased working memory performance. This unexpected finding stresses the importance of incorporating insights from basic research on the mechanisms and preconditions of successful tDCS in future study designs to advance application of tDCS in pediatric ADHD. TRIAL REGISTRATION: German Clinical Trials Register ID: DRKS00012659.