Aim The response to donepezil in patients with Alzheimer's disease varies, and it is important to identify the potential responder before therapy. Cerebral white matter changes (WMC) are frequently observed in older patients, and the effect of WMC on therapeutic response remains controversial. The present study aimed to investigate the relationships between the location of WMC, severe WMC and the response to donepezil. Methods Among 418 patients with Alzheimer's disease receiving donepezil, 196 patients were eligible for analysis. Five brain areas on each side were analyzed using computed tomography scans and the Age‐Related White Matter Changes Rating Scale before therapy. The Cognitive Abilities Screening Instrument was used annually. Patients were defined as responders if their baseline Cognitive Abilities Screening Instrument score minus their follow‐up Cognitive Abilities Screening Instrument score was ≤0. Results There was no significant difference in demographic data between responder and non‐responder groups. Patients in the responder group had significantly less involvement of WMC in the frontal area (P = 0.0213) and nearly a trend for less involvement of WMC in the basal ganglia (P = 0.1103). After adjustment for age, sex, education, polymorphism of apolipoprotein E, hypertension and diabetes, WMC in the frontal area (OR 0.446, P = 0.0139) and basal ganglia (OR 0.243, P = 0.0380) were significantly associated with a reduced therapeutic response. Conclusions Patients with WMC in the frontal area and basal ganglia had significant decreases in their therapeutic response to donepezil. The location of WMC, independent of their severity, might be associated with the therapeutic response in patient with Alzheimer's disease. Geriatr Gerontol Int 2017; ••: ••–••.