Objective: The current study examined the impact of risperidone and divalproex on affective and working memory circuitry in patients with pediatric bipolar disorder (PBD). Method: This was a six-week, double-blind, randomized trial of risperidone plus placebo versus divalproex plus placebo for patients with mania (n = 21; 13.6 [plus or minus] 2.5 years of age). Functional magnetic resonance imaging (fMRI) outcomes were measured using a block design, affective, N-back task with angry, happy, and neutral face stimuli at baseline and at 6-week follow-up. Matched healthy controls (HC; n = 15, 14.5 [plus or minus] 2.8 years) were also scanned twice. Results: In post hoc analyses on the significant interaction in a 3x2x2 analysis of variance (ANOVA) that included patient groups and HC, the risperidone group showed greater activation after treatment in response to the angry face condition in the left subgenual anterior cingulate cortex (ACC) and striatum relative to the divalproex group. The divalproex group showed greater activation relative to the risperidone group in the left inferior frontal gyrus and right middle temporal gyrus. Over the treatment course, the risperidone group showed greater change in activation in the left ventral striatum than the divalproex group, and the divalproex group showed greater activation change in left inferior frontal gyrus and right middle temporal gyrus than the risperidone group. Furthermore, each patient group showed increased activation relative to HC in fronto-striato-temporal regions over time. The happy face condition was potentially less emotionally challenging in this study and did not elicit notable findings. Conclusions: When patients performed a working memory task under emotional duress inherent in the paradigm, divalproex enhanced activation in a fronto-temporal circuit whereas risperidone increased activation in the dopamine (D[subscript 2]) receptor-rich ventral striatum. Clinical trial registration information--Risperidone and Divalproex Sodium With MRI Assessment in Pediatric Bipolar; http://www.clinicaltrials.gov; NCT00176202. (Contains 3 figures and 9 tables.)