Objective Subfield-specific measurements provide superior information in the early stages of neurodegenerative diseases compared to global hippocampal measurements. The overall goal was to systematically compare the performance of five representative manual and automated T1 and T2 based subfield labeling techniques in a sub-set of the ADNI2 population. Methods The high resolution T2 weighted hippocampal images (T2-HighRes) and the corresponding T1 images from 106 ADNI2 subjects (41 controls, 57 MCI, 8 AD) were processed as follows. A. T1-based: 1. Freesurfer + Large-Diffeomorphic-Metric-Mapping in combination with shape analysis. 2. FreeSurfer 5.1 subfields using in-vivo atlas. B. T2-HighRes: 1. Model-based subfield segmentation using ex-vivo atlas (FreeSurfer 6.0). 2. T2-based automated multi-atlas segmentation combined with similarity-weighted voting (ASHS). 3. Manual subfield parcellation. Multiple regression analyses were used to calculate effect sizes (ES) for group, amyloid positivity in controls, and associations with cognitive/memory performance for each approach. Results Subfield volumetry was better than whole hippocampal volumetry for the detection of the mild atrophy differences between controls and MCI (ES: 0.27 vs 0.11). T2-HighRes approaches outperformed T1 approaches for the detection of early stage atrophy (ES: 0.27 vs.0.10), amyloid positivity (ES: 0.11 vs 0.04), and cognitive associations (ES: 0.22 vs 0.19). Conclusions T2-HighRes subfield approaches outperformed whole hippocampus and T1 subfield approaches. None of the different T2-HghRes methods tested had a clear advantage over the other methods. Each has strengths and weaknesses that need to be taken into account when deciding which one to use to get the best results from subfield volumetry.