Aims: The main aim of this post hoc analysis was to evaluate whether response to osmotic release oral system (OROS) methylphenidate (OROS-MPH) was moderated by the concomitant use of antidepressants in attention-deficit/hyperactivity disorder (ADHD) adults stabilized on these medicines for the treatment of depression or anxiety disorders, or a history of mood, anxiety, or substance use disorders. Methods: Two hundred and ninety-six subjects were screened for participation; 227 were randomized (112 to OROS-MPH and 115 to placebo), and 223 were analyzed (N= 109 and N= 114 for OROS-MPH and placebo, respectively). Subjects with anxiety disorders and depression treated with a stable medication regimen of non-MAOI antidepressants or benzodiazepines for at least 3 months could be enrolled in the study. Subjects currently receiving pharmacotherapy for anxiety disorders or depression were required to have Hamilton-Depression and Hamilton-Anxiety rating scales below 15 (mild range). Results: Concomitant antidepressant use at baseline was not associated with ADHD response, OROS-MPH dose, study completion rate, adverse effects, or exacerbation of anxiety/depression. We did find nominally significant evidence that a lifetime history of mood (P= 0.09) or anxiety (P= 0.04) disorders was a moderator of ADHD symptoms and that a lifetime history of substance use disorder (P= 0.02) was a potential moderator of dose at endpoint. Discussion and Conclusions: We found few moderating effects in this large clinical trial of OROS-MPH in adults with ADHD, which supports the robustness of the clinical response to OROS-MPH in adult ADHD despite variable clinical pictures.