BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is the most common mental health disorder in youths. Stimulants are the drugs of first choice in the treatment of ADHD. It has been suggested that full costs associated with the treatment of ADHD may be reduced by once-daily administration regimens of stimulants. OBJECTIVES: To estimate the cost effectiveness of treatment with long-acting methylphenidate osmotic release oral system (OROS) [Concerta((R))] for youths with ADHD for whom treatment with immediate-release (IR) methylphenidate is suboptimal. STUDY DESIGN: We developed a Markov model to obtain an incremental cost-effectiveness ratio (ICER). The analysis covered 10 years, with a Markov cycle of 1 day. Costs (in 2005 euros [euro]) included medication, consultations and treatment interventions, and additional costs for attending special education. Quality-adjusted life-years (QALYs) were used as the effectiveness measure. Outcome probabilities were taken from the medical literature and an expert panel of five child psychiatrists and paediatricians. Univariate sensitivity analyses were performed to assess the robustness of the base-case estimate. Multivariate sensitivity analysis was used to estimate a worst- and best-case ICER. RESULTS: The ICER of methylphenidate-OROS treatment in youths with ADHD for whom treatment with IR methylphenidate is suboptimal was euro2004 per QALY. Total costs after 10 years were euro15 739 for the IR methylphenidate pathway and euro16 015 for the methylphenidate-OROS pathway. In the univariate sensitivity analysis, the ICER was sensitive to changes in resource use and the probability of stopping stimulant treatment in favour of IR methylphenidate. An ICER of 0 was reached with a 6.2% price reduction of methylphenidate-OROS. CONCLUSION: Methylphenidate-OROS is a cost-effective treatment for youths with ADHD for whom treatment with IR methylphenidate is suboptimal. Higher medication costs of methylphenidate-OROS were compensated for by savings on resource use, yielding similar 10-year costs compared with treatment with IR methylphenidate. Our analysis is sensitive to both clinical parameters and (differences in) resource utilization and costs between the groups modelled, warranting further research within clinical trials and observational databases, and into the full scope of costs.