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Objectives A secondary objective of this head-to-head study of lisdexamfetamine dimesylate (LDX) and atomoxetine (ATX) was to assess treatment response rates in children and adolescents with attention-deficit hyperactivity disorder (ADHD) and an inadequate response to methylphenidate (MPH). The primary efficacy and safety outcomes of the study, SPD489-317 (ClinicalTrials.gov NCT01106430), have been published previously. Methods In this 9-week, double-blind, active-controlled study, patients aged 6-17 years with a previous inadequate response to MPH were randomized (1:1) to dose-optimized LDX (30, 50 or 70 mg/day) or ATX (patients < 70 kg: 0.5-1.2 mg/kg/day, not to exceed 1.4 mg/kg/day; patients = 25, >= 30 or >= 50 %) or a Clinical Global Impressions (CGI)-Improvement (CGI-I) score of 1 or 2 throughout weeks 4-9. CGI-Severity (CGI-S) scores were also assessed, as an indicator of remission. Results A total of 267 patients were enrolled (LDX, n = 133; ATX, n = 134) and 200 completed the study (LDX, n = 99; ATX, n = 101). By week 9, significantly (p < 0.01) greater proportions of patients receiving LDX than ATX met the response criteria of a reduction from baseline in ADHD-RS-IV total score of at least 25 % (90.5 vs. 76.7 %), 30 % (88.1 vs. 73.7 %) or 50 % (73.0 vs. 50.4 %). Sustained response rates were also significantly (p < 0.05) higher among LDX-treated patients (ADHD-RS-IV >= 25, 66.1 %; ADHD-RS-IV >= 30, 61.4 %; ADHD-RS-IV >= 50, 41.7 %; CGI-I, 52.0 %) than among ATX-treated individuals (ADHD-RS-IV >= 25, 51.1 %; ADHD-RS-IV >= 30, 47.4 %; ADHD-RS-IV >= 50, 23.7 %; CGI-I, 39.3 %). Finally, by week 9, 60.7 % of patients receiving LDX and 46.3 % of those receiving ATX had a CGI-S score of 1 (normal, not at all ill) or 2 (borderline mentally ill), and greater proportions of patients in the LDX group than the ATX group experienced a reduction from baseline of at least one CGI-S category. Conclusions Both LDX and ATX treatment were associated with high levels of treatment response in children and adolescents with ADHD and a previous inadequate response to MPH. However, within the parameters of the study, LDX was associated with significantly higher treatment response rates than ATX across all response criteria examined. In addition, higher proportions of patients in the LDX group than the ATX group had a CGI-S score of 1 or 2 by week 9, indicating remission of symptoms. Both treatments were generally well tolerated, with safety profiles consistent with those observed in previous studies., This study was supported by funding from Shire. The authors thank the patients and their parents, and the investigators who took part in the study. Esther Cardo, David R. Coghill, Ralf W. Dittmann and Peter Nagy were principal investigators in this clinical study. Colleen S. Anderson, Beatriz Caballero, Richard Civil, Ralf W. Dittmann and Paul Hodgkins contributed to the study design. Ben Adeyi was responsible for the statistical analysis. All authors were involved in the discussion and interpretation of the data, critically revised the article and approved the manuscript before submission. Dr Tamzin Gristwood and Dr Eric Southam of Oxford PharmaGenesis (TM) Ltd provided writing and editing assistance, collated the comments of the authors and edited the manuscript for submission, with funding from Shire. Ben Adeyi, Colleen S. Anderson and Beatriz Caballero are employees of Shire and own stock/stock options. Richard Civil is a former employee of Shire. Paul Hodgkins is a former employee of Shire and a current employee of Vertex Pharmaceuticals. The following authors have received compensation for serving as consultants or speakers, or they, or the institutions they work for, have received research support or royalties from the companies or organizations indicated: Esther Cardo (Eli Lilly, Health Spanish Ministry Research Fund, Ministry of Education Grant Research, Shire, UCB); David R. Coghill (Flynn Pharma, Janssen-Cilag, Lilly, Medice, Novartis, Otsuka, Oxford University Press, Pfizer, Schering-Plough, Shire, UCB, Vifor Pharma); Ralf W. Dittmann (Ferring, Janssen-Cilag, Lilly, Otsuka, Shire, German Research Foundation [DFG], German Ministry of Education and Research [BMBF], Ministry of Health/German Regulatory Body [BfArM], European Union [EU FP7 program], US National Institute of Mental Health (NIMH), and he is a former employee and stock-holder of Eli Lilly and Co.); Peter Nagy (Tourette Syndrome Association of USA, Hungarian Ministry of Education, National Development Agency of Hungary, Otsuka, Shire).