Although the patterns of structural and metabolic brain alterations in Alzheimer's disease are being refined and discrepancies between them are being underlined, the exact relationships between atrophy and hypometabolism are still unclear. In this study, we aimed to provide a direct comparison between grey matter atrophy and hypometabolism in a sample of patients with clinically probable Alzheimer's disease, using a voxel-based method specially designed to statistically compare the two imaging modalities. Eighteen patients with probable Alzheimer's disease of mild severity and 15 healthy aged controls underwent both high-resolution T1 MRI and resting-state (18)FDG-PET. The MRI data sets were handled using optimized VBM. The PET data were coregistered to their corresponding MRI, corrected voxel-wise for partial volume averaging and spatially normalized using the same parameters as those of their corresponding MRI volume. A differential smoothing was applied on the MRI and PET data sets to equalize their effective smoothness and resolution. For each patient, Z-score maps of atrophy and hypometabolism were created by comparing to the controls data set, respectively averaged to provide the profile of hypometabolism and atrophy, and entered in a voxel-by-voxel SPM analysis to assess the statistical differences between hypometabolism and atrophy. The observed patterns of hypometabolism and atrophy were consistent with previous studies. However, the direct comparison revealed marked regional variability in the relationship between hypometabolism and atrophy. Thus, the hypometabolism significantly exceeded atrophy in most altered structures, particularly in the posterior cingulate-precuneus, orbitofrontal, inferior temporo-parietal, parahippocampal, angular and fusiform areas. In contrast, a few hypometabolic structures among which the hippocampus exhibited similar degrees of atrophy and hypometabolism, a profile that significantly differed from the posterior cingulate. Excessive hypometabolism relative to atrophy suggests the intervention of additional hypometabolism-inducing factors, such as disconnection and amyloid deposition, resulting in genuine functional perturbation ahead of actual atrophy and perhaps of pathology as well. Conversely, in the hippocampus, where disconnection processes are also likely to occur, relative synaptic compensatory mechanisms may be taking place, maintaining neuronal activity in the face of structural alterations.