We conducted semiautomated, atlas-based analyses of regional brain volume changes on MRIs of children and adolescents with Down syndrome (DS) (N=15), DS with comorbid autism spectrum disorder (ASD) (N=15), and age-matched or sex-matched typically developing controls (N=22). Selective volumetric changes were correlated with neurobehavioral measures to determine their functional significance. DS involved selective reduction of frontal and parietal gray matter volumes, beyond the global microencephaly typically observed in this condition. DS with comorbid ASD involved relative hyperplasia of white matter in the cerebellum and brainstem compared with DS only. Cerebellar white matter volumes were positively correlated with severity of stereotypies, a distinctive feature of ASD in DS.