Objective: To examine lisdexamfetamine dimesylate (LDX) efficacy and safety versus placebo in adolescents with attention-deficit/hyperactivity disorder (ADHD). Method: Adolescents (13 through 17) with at least moderately symptomatic ADHD (ADHD Rating Scale IV: Clinician Version [ADHD-RS-IV] score greater than or equal to 28) were randomized to placebo or LDX (30, 50, or 70 mg/d) in a 4-week, forced-dose titration, double-blind study. Primary and secondary efficacy measures were the ADHD-RS-IV, Clinical Global Impressions-Improvement (CGI-I), and Youth QOL--Research Version (YQOL-R). Safety assessments included treatment-emergent adverse events (TEAEs), vital signs, laboratory findings, physical examinations, and ECG. Results: Overall, 314 participants were randomized; 309 were in efficacy analyses and 49 withdrew (11 due to TEAEs). Least squares mean (SE) change from baseline at endpoint in ADHD-RS-IV total scores were -18.3 (1.25), -21.1 (1.28), -20.7 (1.25) for 30, 50, and 70 mg/d LDX, respectively; -12.8 (1.25) for placebo (p less than or equal to 0.0056 versus placebo for each). Differences in ADHD-RS-IV total scores favored all LDX doses versus placebo at all weeks (p less than or equal to 0.0076). On the CGI-I, 69.1% of participants were rated very much/much improved at endpoint with LDX all doses versus placebo (39.5%) (p less than 0.0001). YQOL-R changes at endpoint scores for LDX groups versus placebo were not significant. Commonly reported LDX (all doses combined) TEAEs (greater than or equal to 5%) were decreased appetite, headache, insomnia, decreased weight, and irritability. Small mean increases in pulse and blood pressure and no clinically meaningful trends in ECG changes were noted with LDX. Conclusions: LDX at all doses was effective versus placebo in treating adolescent ADHD and demonstrated a safety profile consistent with previous LDX studies. (Contains 3 tables and 2 figures.)