Quantitative MRI of the hippocampus has been increasingly employed as a biomarker in Alzheimer's disease (AD). We compare voxel-based morphometry (VBM) standard and DARTEL registration with manual hippocampal volumetry in AD patients and cognitively normal older adults. Participants were 20 cognitively normal elderly subjects and 19 AD patients who met the criteria of probable AD according to NINCDS-ADRDA. Bilateral manual hippocampal volumetry was conducted alongside VBM of hippocampal regions-of-interest (ROIs) generated with standard and DARTEL registration using hippocampal masks and total intracranial volume normalization. All normalized hippocampal measurements showed significant reduction (20–30%; p < 0.001) in AD compared to controls. Logistic regression analysis also showed significant effects (odds ratios ranged from 88.2% to 94.0%) of all normalized measurements in predicting AD incidence after adjusting for age, gender, and education. The overall prediction accuracies of manual RH and LH volumes, standard RH-ROI and LH-ROI VBM, DARTEL RH-ROI, and LH-ROI VBM were 87.2%, 84.6%, 87.2%, 76.9%, 87.2%, and 87.2%, respectively. As imaging biomarkers, VBM with DARTEL and standard registration have similarly high efficacies as manual hippocampal volumetry in discriminating AD from cognitively normal elderly adults.