Objective: To compare longitudinal changes in the hippocampal structure in subjects with very mild dementia of the Alzheimer type (DAT) treated with donepezil hydrochloride, untreated subjects with very mild DAT, and controls without dementia. Design: MPRAGE sequences were collected approximately 2 years apart on two 1.5-T magnetic resonance imaging systems, yielding 2 cohorts. Large-deformation high-dimensional brain mapping was used to compute deformation of hippocampal subfields. Setting: A dementia clinic at Washington University School of Medicine. Patients or Other Participants: Subjects came from 2 sources: 18 untreated subjects with DAT and 26 controls were drawn from a previous longitudinal study; 18 treated subjects with DAT were studied prospectively, and 44 controls were drawn from a longitudinal study from the same period. Intervention: Patients were prescribed donepezil by their physician. Main Outcome Measures: Hippocampal volume loss and surface deformation. Results: There was no significant cohort effect at baseline; therefore, the 2 groups of control subjects were combined. The potential confounding effect of cohort/ scanner was dealt with by including it as a covariate in statistical tests. There was no significant group effect in the rate of change of hippocampal volume or subfield deformation. Further exploration showed that compared with the untreated subjects with DAT, the treated subjects with DAT did not differ in the rate of change in any of the hippocampal measures. They also did not differ from the controls, while the untreated subjects with DAT differed from the controls in the rates of change of hippocampal volume and CA1 and subiculum subfield deformations. Conclusions: Treatment with donepezil did not alter the progression of hippocampal deformation in subjects with DAT in this study. Small sample size may have contributed to this outcome.