OBJECTIVES: To evaluate the cost-effectiveness of GXR vs. ATX for the treatment of ADHD in children and adolescents from a US third-party payer perspective.  METHODS: An economic model was developed to estimate the cost effectiveness of GXR vs. ATX during a 4-week drug titration period and a 48-week maintenance period (one-year time horizon). Effectiveness was measured by the number of responders (defined as patients with ≥25% reduction in ADHD-Rating Scale-IV total observed score compared to baseline), and estimated quality-adjusted life years (QALYs). The model assumed all patients received treatment until the end of titration and only responders continued treatment afterwards. A uniform constant discontinuation rate, based on the long-term trials of GXR and ATX, was applied. Response rates were obtained from a matching-adjusted indirect comparison of efficacy between GXR and ATX based on the Phase III trials. Published utilities corresponding to response and non-response health states were applied. Disutility due to adverse events was applied to the entire titration period. Costs included published drug wholesale acquisition costs (WAC) in 2010 US dollars. Incremental cost per QALY and incremental cost per responder were estimated for GXR compared to ATX. Various one-way sensitivity analyses (SA) were conducted to examine the robustness of the model.  RESULTS: Despite the lower WAC unit price, GXR had an incremental cost of $171 over ATX because more GXR patients achieved response and continued treatment. In the base case, the cost/QALY was $24,688 and the incremental cost per responder was $1,979. Most scenarios in the one-way SA resulted in a cost/QALY below $50,000, with the exceptions of increasing GXR or decreasing ATX costs by 25%.  CONCLUSIONS: Compared to ATX, GXR is cost-effective, at the cost that is lower than the socially acceptable willingness-to-pay threshold of $50,000/QALY, for the treatment of ADHD in children and adolescents.