Introduction <p>This post-marketing surveillance study assessed the safety and effectiveness of guanfacine hydrochloride extended-release (GXR) in adults with attention-deficit/hyperactivity disorder (ADHD) in routine clinical practice in Japan.</p> Methods <p>In this prospective, multicenter study, adults (≥ 18&#xa0;years) were followed for 1&#xa0;year after initiating GXR treatment or until treatment discontinuation, whichever occurred first (enrollment: June 2020–March 2022). Hypotension and bradycardia, syncope, blood pressure elevation upon discontinuation, and QT prolongation were key safety concerns for evaluation. Missing data were not imputed; therefore, effectiveness outcomes reflect only the observed data.</p> Results <p>In total, 961 patients were enrolled across 155 sites; case report forms were collected for 949 patients. Of these, 912 and 784 were included in the safety and effectiveness analyses, respectively. The 12-month GXR continuation rate was 45.2%. Adverse drug reactions (ADRs) reported in ≥ 1% of patients were somnolence (15.02%), dizziness (3.95%), malaise (3.73%), postural dizziness (2.85%), thirst (2.52%), decreased blood pressure (1.86%), hypotension (1.54%), and constipation (1.43%). Seventeen serious ADRs occurred in 13 patients: bradycardia, cerebral ischemia, mental impairment, and syncope (<i>n</i> = 2 each) and decreased blood pressure, delusions, dizziness, postural dizziness, erectile dysfunction, hallucination, psychomotor hyperactivity, somnolence, and suicidal ideation (<i>n</i> = 1 each). Forty-one patients (4.50%) experienced 42 hypotension and bradycardia events (3 were serious). Two patients (0.22%) experienced a syncope event (preferred term: syncope); although both were assessed as non-serious by the investigator, they were classified as serious per the Important Medical Events list. In accordance with the Japanese Risk Management Plan, these two events were also recorded as QT prolongation events (preferred term: syncope). Improvement rates in Clinical Global Impression-Improvement and Patient Global Impression-Improvement scales increased over the 1-year observation period. ADHD-Rating Scale-IV total and subscale scores also improved over time, with significant improvements from baseline observed at all time points (<i>p</i> &lt; 0.0001).</p> Conclusions <p>No ADRs requiring new safety measures were observed. The effectiveness of GXR in adult ADHD was evident among patients remaining on treatment.</p> Trial Registration <p>UMIN Clinical Trials Registry (identifier: UMIN000040429).</p>