Background. Problems with cognitive flexibility have been observed in patients with attention deficit hyperactivity disorder (ADHD) and in patients with conduct disorder (CD), characterized by the violation of societal rules and the rights of others. Functional magnetic resonance imaging (fMRI) of cognitive switching, however, has only been investigated in patients with ADHD, including comorbidity with CD, finding frontostriatal and temporoparietal underactivation. This study investigates disorder-specific functional abnormalities during cognitive flexibility between medication-naive children and adolescents with noncomorbid CD and those with noncomorbid ADHD compared to healthy controls. Methods. Event-related fMRI was used to compare brain activation of 14 boys with noncomorbid, childhood-onset CD, 14 boys with noncomorbid ADHD, and 20 healthy comparison boys during a visual-spatial Switch task. Results. Behaviorally, children with ADHD compared to children with CD had significantly slower reaction times to switch compared to repeat trials. The fMRI comparison showed that the patients with ADHD compared to both controls and patients with CD showed underactivation in right and left inferior prefrontal cortex. No disorder-specific brain underactivation was observed in patients with CD. Only when compared with controls alone, the disruptive behavior group showed reduced activation in bilateral temporoparietal and occipital brain regions. Conclusions. The findings extend previous evidence for disorder-specific underactivation in patients with ADHD compared to patients with CD in inferior prefrontal cortex during tasks of inhibitory control to the domain of cognitive flexibility. Inferior prefrontal underactivation thus appears to be a disorder-specific neurofunctional biomarker for ADHD when compared with patients with CD. Hum Brain Mapp 31:1823-1833, 2010. (C) 2010 Wiley-Liss, Inc.