BACKGROUND: Economic evaluations of treatments for children with behavioural difficulties (i.e., characteristics of attention-deficit/hyperactivity disorder (ADHD) and/or oppositional defiant disorder (ODD)) usually rely on data of randomised controlled trials or are model-based. Findings of such studies may not be representative of cost-effectiveness and cost-utility in clinical practice. The current longitudinal study aimed to perform an economic evaluation of treatments for children with hyperactivity, impulsive behaviours, inattention, and/or behavioural difficulties using observational data that were obtained in clinical practice. METHODS: Parents of 209 children (aged 5-12) who were referred to 1 of 10 Dutch youth mental healthcare institutions and who received treatment with (n = 108) or without (n = 101) the use of medication, filled out questionnaires at three timepoints (baseline, and ~ 6 and ~12 months later). Propensity score matching was used to make both groups comparable. Outcomes included quality-adjusted life years (QALYs), ADHD and ODD symptom severity, and impairment. Costs were measured from a societal perspective. Incremental cost-effectiveness ratios (ICERs) were estimated, and cost-effectiveness acceptability curves (CEACs) were derived to show uncertainty around the ICER. RESULTS: Results did not show statistically significant differences in costs and effects between children who were treated with medication (alone or in combination with non-medication treatment) and those who were treated without medication. CEAC suggested that medication treatment has a 55% probability of being cost-effective at the €80,000 threshold and 36% at the €20,000 threshold compared with treatment without medication. CONCLUSIONS: Using observational data, our study did not provide clear evidence of the cost-effectiveness and cost-utility of treatment with medication compared with treatment without medication in clinical practice.