OBJECTIVE To assess the association of Medial Temporal lobe Atrophy (MTA) and White Matter Hyperintensities (WMHs) with gray matter perfusion in Mild Cognitive Impairment (MCI). METHODS 56 MCI patients (age = 69.3 +/- 7.0, 32 females) underwent brain MR scan and (99m)Tc ECD SPECT. We evaluated MTA according to Scheltens' fivepoint scale on T1 MR images, and assessed WMHs using the rating scale for age-related white matter changes on T2-weighted and FLAIR MR images. We divided MCI into age-matched subgroups with high and low MTA and high and low WMHs load. We processed SPECT images with SPM2 following an optimized protocol and performed a voxel-based statistical analysis comparing high vs. low MTA and high vs. low WMHs, setting p-value at 0.001 uncorrected, thresholding cluster extent at 100 voxels, using proportional scaling and entering age and WMHs or MTA respectively as nuisance covariates. RESULTS MCI with high compared with low MTA showed hypoperfusion in the left hippocampus and in the left parahippocampal gyrus. MCI with high compared with low WMHs showed a hypoperfusion area in the left insular region and superior temporal gyrus. CONCLUSIONS MTA in MCI is associated with hippocampal gray matter hypoperfusion while WMHs is associated with gray matter hypoperfusion in areas of the insula and temporal neocortex. These results confirm that MTA is associated with local functional changes and suggest that WMHs may be associated with remote brain cortical dysfunction.