Objective: To investigate the influence of microglial activation in the early stages of Alzheimer’s disease trajectory, we assessed the relationship between microglial activation and grey matter volume and hippocampal volume in MCI patients. Methods: In this study, fifty-five participants (37 early stages MCI and 18 controls) underwent [11C]PBR28 PET, a marker of microglial activation; volumetric MRI to evaluate grey matter and hippocampal volumes as well as clinical and neuropsychometric evaluation. [11C]PBR28 VT (volume of distribution) was calculated using arterial input function and Logan Graphical analysis. Grey matter volume and hippocampal volumes were calculated from MRI for each subject. Statistical parametric mapping software was used to perform voxel-wise correlations and biological parametric mapping analysis. Amyloid status was assessed using [18F]Flutemetamol PET. Results: Higher [11C]PBR28 VT in different cortical areas correlated with higher grey matter volume in both amyloid positive and negative MCI. Additionally, higher hippocampal volume correlated with higher cortical [11C]PBR28 Logan VT. Conclusions: In this in vivo study, we have demonstrated that microglial activation quantified using [11C]PBR28 PET was associated with higher grey matter volume and higher hippocampal volume in MCI patients. This may suggest that microglial activation may not always be associated with neuronal damage, and indeed it may have beneficial effect in early stages of Alzheimer’s trajectory. While further longitudinal studies are necessary, these findings have significant implications on therapeutic strategies targeting microglial activation.