Background: Inhibiting prepotent responses is critical to optimal cognitive and behavioral function across many domains. Several behavioral studies have investigated response inhibition in autism, and the findings varied according to the components involved in inhibition. There has been only one published functional magnetic resonance imaging (fMRI) study so far on inhibition in autism, which found greater activation in participants with autism than control participants. Methods: This study investigated the neural basis of response inhibition in 12 high-functioning adults with autism and 12 age- and intelligence quotient (IQ)-matched control participants during a simple response inhibition task and an inhibition task involving working memory. Results: In both inhibition tasks, the participants with autism showed less brain activation than control participants in areas often found to be active in response inhibition tasks, namely the anterior cingulate cortex. In the more demanding inhibition condition, involving working memory, the participants with autism showed more activation than control participants in the premotor areas. In addition to the activation differences, the participants with autism showed lower levels of synchronization between the inhibition network (anterior cingulate gyrus, middle cingulate gyrus, and insula) and the right middle and inferior frontal and right inferior parietal regions. Conclusions: The results indicate that the inhibition circuitry in the autism group is activated atypically and is less synchronized, leaving inhibition to be accomplished by strategic control rather than automatically. At the behavioral level, there was no difference between the groups. © 2007 Society of Biological Psychiatry.