Objective: To investigate the effects of methylphenidate (MPH) on components of working memory (WM) in children with ADHD and determine whether MPH produces differential effects on WM in children with comorbid anxiety (ANX). Method: Participants were a clinical sample of 130 children with ADHD, aged 6 to 12 years old (32% comorbid ANX). Each child participated in an acute randomized, double-blind, placebo-controlled, crossover trial with single challenges of three MPH doses. Four WM measures were used that varied in processing demands (storage versus manipulation of information) and modality (auditory-verbal; visual-spatial). Results: MPH improved auditory-verbal manipulation but only in the non-ANX children with ADHD. It had no effect on auditory-verbal storage of information. Also, MPH improved the ability to manipulate visual-spatial information in both ADHD groups, but beneficial effects on visual-spatial storage were evident only in children without comorbid ANX. Conclusions: Findings provide insight into potential mechanisms underlying individual differences in treatment response in ADHD, which may facilitate more targeted treatments. (Contains 3 tables.)