Previous structural brain imaging studies of Down Syndrome (DS) have offered important insights into the underlying morphometric aberrations associated with the condition. These previous studies have relied almost exclusively on classic region-of-interest (ROI)-based morphometry, a method in which a finite number of anatomical structures must be defined and delineated a priori. Here we use the fully automated voxel-based morphometry (VBM) approach on 19 nondemented individuals with DS and 11 age-matched controls in order to provide a full-brain assessment of DS morphology. Foci of statistically significant (P < 0.05, corrected for multiple comparisons) reductions in gray matter (GM) tissue were observed in the cerebellum, cingulate gyrus, left medial frontal lobe, right middle/superior temporal gyrus, and the left CA2/CA3 region of the hippocampus. Significant decreases in white matter (WM) tissue were noted throughout the inferior brainstem. Foci of statistically significant (P < 0.05, corrected for multiple comparisons) increases in GM tissue were observed in a superior/caudal portion of the brainstem and left parahippocampal gyrus. Significant increases in WM tissue were noted bilaterally in the parahippocampal gyrus. We also noted significant increases in cerebral spinal fluid in regions suggesting enlarged lateral ventricles in the DS group. While these results are generally consistent with prior ROI-based imaging studies of nondemented DS individuals, the present findings provide additional understanding of the three-dimensional topography of DS morphology throughout the brain. The consistency of these findings with prior imaging reports demonstrates the utility of the VBM technique for investigating the neuroanatomy of DS.