OBJECTIVES: An economic analysis was conducted from the United Kingdom’s (UK’s) National Health Service (NHS) perspective to evaluate the cost-effectiveness of lisdexamfetamine (LDX) versus atomoxetine (ATX) in treating children and adolescents with attention-deficit/hyperactivity disorder (ADHD) who have had an inadequate response to methylphenidate (MPH).  METHODS: A 1-year probabilistic decision-analytic model with a Markov structure of nested decision trees was constructed. Health states included ”response”, “non-response”, and “unable to tolerate”. Key model assumptions were adapted from a technology assessment for ADHD products by the National Institute for Health and Care Excellence. The analysis used clinical data from a head-to-head randomized controlled trial in inadequate responders to MPH. Response to treatment was defined as a score of 1 (much improved) or 2 (improved) on the Clinical Global Impression-Improvement scale. Tolerability was assessed by rates of discontinuation due to adverse events. Utility weights were identified via a systematic literature review. Healthcare resource use estimates for responders and non-responders were obtained via a survey of UK specialists. Unit costs from national sources were applied to estimate the corresponding health-state costs. Daily drug costs were based on mean doses reported in the trial. One-way and probabilistic sensitivity analyses were performed.  RESULTS: The comparison of LDX and ATX, using head-to-head data, resulted in an incremental cost-effectiveness ratio (ICER) of £1,802 per quality-adjusted life year (QALY). At a willingness to pay of £20,000 per QALY, LDX had an 86% probability of being cost-effective compared with ATX. In 38% of sensitivity analysis runs, LDX was a dominant strategy over ATX. The model was slightly sensitive to changes in assumptions about drug costing and to lengthening the titration period for ATX.  CONCLUSIONS: From the perspective of the UK NHS, LDX provides a cost-effective treatment option for children and adolescents with ADHD who are inadequate responders to MPH.