OBJECTIVES: Although many treatments for ADHD are used off-label, in the United Kingdom, only atomoxetine (ATX), dexamphetamine (DEX), and methylphenidate (MPH) are licensed for use in children and adolescents. The objective of this review was to systematically review and synthesise the existing clinical evidence, by indirectly comparing the licensed treatments and a drug in development, lisdexamfetamine (LDX).  METHODS: A systematic review of randomised controlled clinical trials, dated 1960 or later, in children and adolescents with ADHD that included at least one of LDX, MPH, DEX, or ATX was performed. Network meta-analysis methods for dichotomous outcomes were employed to evaluate treatment efficacy (response defined by either the ADHD Rating Scale [ADHD-RS] or Clinical Global Impression–Improvement scale [CGI-I]) and safety outcomes (all cause withdrawals [WDW] and withdrawal due to adverse events [AEWDW]).  RESULTS: The systematic review included 32 trials, dated 2000 or later, including data on LDX, ATX, and MPH (extended release [MPH-ER], intermediate release [MPH-intR] and immediate release [MPH-IR]). No trials for DEX meeting the inclusion criteria were found. Sufficient data were identified for each of the outcomes: ADHD-RS, 16 trials; CGI-I, 20 trials; WDW, 28 trials; and AEWDW, 27 trials. The efficacy relative risks (95% confidence intervals [CI]) for LDX versus ATX were ADHD-RS, 1.41 (1.24, 1.61); CGI-I, 1.55 (1.28, 1.87); and for LDX versus MPH-ER (the most commonly used MPH formulation) were ADHD-RS, 1.22 (1.08, 1.38); and CGI-I, 1.23 (1.04, 1.45). The safety relative risks (95% confidence intervals [CI]) for LDX versus ATX were WDW, 0.75 (0.49, 1.17); AEWDW, 1.72 (0.46, 6.37); and for LDX versus MPH-ER were WDW: 1.15 (0.74, 1.78), and AEWDW: 2.70 (0.75, 9.71).  CONCLUSIONS: The evidence synthesis of efficacy favours LDX over ATX and MPH-ER for the treatment of ADHD. The analysis of safety data proved inconclusive due to small event rates.