© 2014 The Authors. Despite substantial clinical and anecdotal evidence for emotion dysregulation in individuals with autism spectrum disorder (ASD), little is known about the neural substrates underlying this phenomenon. We sought to explore neural mechanisms for cognitive reappraisal in children and adolescents with ASD using functional magnetic resonance imaging (fMRI). We studied 16 youth with ASD and 15 age- and IQ-matched typically developing (TD) comparison youth. Participants were instructed in the use of cognitive reappraisal strategies to increase and decrease their emotional responses to disgusting images. Participants in both groups displayed distinct patterns of brain activity for increasing versus decreasing their emotions. TD participants showed downregulation of bilateral insula and left amygdala on decrease trials, whereas ASD participants showed no modulation of insula and upregulation of left amygdala. Furthermore, TD youth exhibited increased functional connectivity between amygdala and ventrolateral prefrontal cortex compared to ASD participants when downregulating disgust, as well as decreased functional connectivity between amygdala and orbitofrontal cortex. These findings have important implications for our understanding of emotion dysregulation and its treatment in ASD. In particular, the relative lack of prefrontal-amygdala connectivity provides a potential target for treatment-related outcome measurements.