Background: Although the pattern of frontal electroencephalogram (EEG) asymmetry during the processing of emotion has been examined in many studies of healthy adults and typically developing infants and children, no published work has used these theoretical and methodological approaches to study emotion processing in children with Down syndrome. The purpose of this pilot study was to examine the feasibility of using brain-based measures of emotion (i.e. regional EEG asymmetry measures) with children with Down syndrome, and whether children with Down syndrome exhibit patterns of frontal brain activity during the processing of affective stimuli that are not different from typically developing children, but of lesser magnitude. Methods: Regional brain electrical activity (EEG) was measured in response to the presentation of popular children's video clips that varied in affective content in three children with Down syndrome and three typically developing children who were matched on reading level. Results: The children with Down syndrome appeared to show a similar pattern of frontal EEG asymmetry as the typically developing children for the video clips depicting happiness, sadness and fear. However, the magnitude of the frontal asymmetry scores for the children with Down syndrome was large across the affective stimuli, and they appeared to process the video clip depicting anger differently from the typically developing children. Conclusion: This preliminary evidence suggests that brain-based measures of affective processing can be used to study the differentiation of emotion on an electrocortical level among children with Down syndrome.