OBJECTIVES: Attention deficit/hyperactivity disorder (ADHD) is a common psychiatric disorder with substantial clinical and economic implications.  While psychostimulants are first-line pharmacologic treatment, up to 30% of ADHD children have suboptimal response to psychostimulants and require adjunctive therapy.  Our objective was to analyze the cost-effectiveness of adding an alpha-2A agonist, guanfacine extended release (GXR), to long-acting psychostimulants vs. maintaining existing long-acting psychostimulant monotherapy in children and adolescents with ADHD and suboptimal response to psychostimulant monotherapy. METHODS: A one-year Markov model was developed from a US third-party payer perspective. Effectiveness was measured by quality-adjusted life year (QALY). The model assumed patients transitioned among four health states (normal, mild, moderate, and severe), defined based on the Clinical Global Impressions-Severity (CGI-S) scale. Transition probabilities were estimated in an ordered logit model using patient-level data from a Phase III clinical trial comparing psychostimulants plus GXR with psychostimulants plus placebo (n=461). The model assumed that patients in moderate or severe states after week eight would discontinue ADHD treatment and remain in that state. Direct costs included drug wholesale acquisition costs (WAC) and medical costs, in 2010 US dollars. Health state utilities were obtained from the literature. Disutilities associated with adverse events were applied for the first four weeks. One-way sensitivity analyses (SA) were conducted by varying key model inputs. RESULTS: Adding GXR to existing psychostimulant monotherapy was associated with an incremental drug cost of $1016 but lower medical cost of $124, resulting in a total one-year incremental cost of $892. The addition of GXR led to an incremental QALY of 0.03 and an incremental cost-effectiveness ratio (ICER) of $31,660/QALY. In one-way SA, ICERs ranged from $19,723/QALY to $46,631/QALY. CONCLUSIONS: This is the first cost-effectiveness analysis of psychostimulants with adjunctive medication. Adjunctive therapy of GXR with psychostimulants is cost-effective based on a willingness-to-pay threshold of $50,000/QALY.