Background Extended‐release guanfacine hydrochloride (GXR), a selective α2A‐adrenergic agonist, is a nonstimulant medication for attention‐deficit/hyperactivity disorder (ADHD). This phase 3, double‐blind, placebo‐controlled, randomised‐withdrawal study evaluated the long‐term maintenance of GXR efficacy in children/adolescents with ADHD. Methods Children/adolescents (6–17 years) with ADHD received open‐label GXR (1–7 mg/day). After 13 weeks, responders were randomised to GXR or placebo in the 26‐week, double‐blind, randomised‐withdrawal phase (RWP). The primary endpoint was the percentage of treatment failure (≥50% increase in ADHD Rating Scale version IV total score and ≥2‐point increase in Clinical Global Impression‐Severity compared with RWP baseline, at two consecutive visits). The key secondary endpoint was time to treatment failure (TTF). Trial registration ClinicalTrials.gov identifier NCT01081145; EudraCT 2009‐018161‐12. Results A total of 528 participants enrolled; 316 (59.8%) entered the RWP. Treatment failure occurred in 49.3% of the GXR and 64.9% of the placebo group (p = 0.006). TTF was significantly longer in GXR versus placebo (p = 0.003). GXR was well tolerated. Conclusions Guanfacine hydrochloride demonstrated long‐term maintenance of efficacy compared with placebo in children/adolescents with ADHD. Implications of the placebo substitution design and findings with different ADHD medications are discussed. Phase 3, double‐blind, placebo‐controlled, randomized‐withdrawal study evaluating the long‐term maintenance of GXR efficacy in children/adolescents with ADHD.