Abstract Voxel-based morphometry (VBM) and automated lobar region of interest (ROI) volumetry are comprehensive and fast methods to detect differences in overall brain anatomy on magnetic resonance images. However, VBM and automated lobar ROI volumetry have detected dissimilar gray matter differences within identical image sets in our own experience and in previous reports. To gain more insight into how diverging results arise and to attempt to establish whether one method is superior to the other, we investigated how differences in spatial scale and in the need to statistically correct for multiple spatial comparisons influence the relative sensitivity of either technique to group differences in gray matter volumes. We assessed the performance of both techniques on a small dataset containing simulated gray matter deficits and additionally on a dataset of 22q11-deletion syndrome patients with schizophrenia (22q11DS-SZ) vs. matched controls. VBM was more sensitive to simulated focal deficits compared to automated ROI volumetry, and could detect global cortical deficits equally well. Moreover, theoretical calculations of VBM and ROI detection sensitivities to focal deficits showed that at increasing ROI size, ROI volumetry suffers more from loss in sensitivity than VBM. Furthermore, VBM and automated ROI found corresponding GM deficits in 22q11DS-SZ patients, except in the parietal lobe. Here, automated lobar ROI volumetry found a significant deficit only after a smaller sub-region of interest was employed. Thus, sensitivity to focal differences is impaired relatively more by averaging over larger volumes in automated ROI methods than by the correction for multiple comparisons in VBM. These findings indicate that VBM is to be preferred over automated lobar-scale ROI volumetry for assessing gray matter volume differences between groups.