OBJECTIVES: Attention-deficit/hyperactivity disorder (ADHD) is a common childhood disorder with a global prevalence of 2.2 to 17.8%. In the case of an inadequate response to stimulant medication, a combination therapy of stimulants and adjunctive medication may improve the control of ADHD symptoms, reduce dose-limiting adverse events, and help manage comorbidities. The objective was to assess the economic impact of guanfacine extended-release (GXR) in combination with long-acting stimulants compared to long-acting stimulant monotherapy in the treatment of children and adolescents with ADHD from a Canadian perspective. METHODS: A Markov model was developed to assess the cost-effectiveness of GXR in combination with a long-acting stimulant compared to long-acting stimulant monotherapy. Health states were defined based on the clinician-reported Clinical Global Impressions-Severity (normal, mild, moderate, and severe). Transition probabilities were calculated based on patient-level data from a published study. Long-acting stimulants available in Canada were considered in the base-case model: amphetamine mixed salts, methylphenidate HCl formulations, and lisdexamfetamine dimesylate. Analyses were conducted from both a Canadian Ministry of Health (MoH) and a societal perspective over a 1-year time horizon with weekly cycles. Deterministic and probabilistic sensitivity analyses (PSA) were conducted to assess the robustness of the base-case results. RESULTS: Compared to long-acting stimulant monotherapy, GXR with a long-acting stimulant was associated with incremental cost-effectiveness ratios of $23,720/QALY and $11,845/QALY from a Canadian MoH and a societal perspective, respectively. PSA of GXR as an adjunctive therapy to long-acting stimulants showed that it remains a cost-effective strategy in 100% of the simulations from both perspectives in numerous sensitivity analyses, according to a willingness to pay of $50,000/QALY. CONCLUSIONS: This economic evaluation demonstrates that GXR as an adjunctive therapy to a long-acting stimulant is a cost-effective strategy compared to long-acting stimulant monotherapy in the treatment of children and adolescents with ADHD in Canada.