Background: Patients with dementia of the Alzheimer type (DAT) respond variably to treatment with acetylcholinesterase inhibitors. Objective: To determine whether measures of hippocampal volume and shape predict the response to donepezil in patients with DAT. Design: T1-weighted, magnetic resonance images were obtained from patients with DAT, who subsequently underwent treatment with donepezil. Brain-mapping algorithms were used to quantify hippocampal volume and shape, and growth curves were used to estimate clinical outcome. Setting: A referral outpatient center specializing in treatment of dementia. Patients: Thirty-seven patients with very mild or mild DAT received donepezil therapy for up to 4 weeks before magnetic resonance imaging and for 24 to 96 weeks after magnetic resonance imaging. Intervention: Donepezil, 10 mg/d. Main Outcome Measure: Rate of change in the cognitive portion of the Alzheimer's Disease Assessment Scale total scores. Results: Smaller hippocampal volume and inward variation of the lateral and inferomedial portions of the hippocampal surface were correlated with a poorer response to donepezil therapy. Conclusions: Measures of hippocampal volume and surface variation can be used to predict the response of patients with DAT to the acetylcholinesterase inhibitor donepezil.