Impulsivity, inattention and poor behavioral inhibition are common deficits in pediatric bipolar disorder (PBD) and attention deficit hyperactivity disorder (ADHD). This study aimed to identify similarities and differences in the neural substrate of response inhibition deficits that are associated with these disorders. A functional magnetic resonance imaging (fMRI) study was conducted on 15 unmedicated PBD patients (Type I, manic/mixed), 11 unmedicated ADHD patients, and 15 healthy controls (HC) (mean age = 13.5 years; S.D. = 3.5). A response inhibition task examined the ability to inhibit a motor response to a target when a stop cue appeared shortly after. The PBD and ADHD groups did not differ on behavioral performance, although both groups were less accurate than the HC group. fMRI findings showed that for trials requiring response inhibition, the ADHD group, relative to the PBD and HC groups, demonstrated reduced activation in both ventrolateral (VLPFC) and dorsolateral (DLPFC) prefrontal cortex, and increased bilateral caudate activation compared with HC. The PBD group, relative to HC, showed decreased activation in the left VLPFC, at the junction of the inferior and middle frontal gyri, and in the right anterior cingulate cortex (ACC). Prefrontal dysfunction was observed in both the ADHD and PBD groups relative to HC, although it was more extensive and accompanied by subcortical overactivity in ADHD.