We evaluated regional cerebral blood flow (rCBF) changes in Alzheimer's disease (AD) as measured by single photon emission computed tomography (SPECT) before and after 12 months of donepezil treatment and determined perfusion patterns associated with the cognitive response to donepezil therapy. The 59 AD patients treated with donepezil over 24 months were divided into the long-term stabilized group (stabilized more than 24 months), the short-term stabilized group (stabilized more than 12 months but worsened within 24 months), and the nonstabilized group (worsened within 12 months) based on mini-mental state examination (MMSE) score changes. SPECT data were analyzed by the three-dimensional stereotactic surface projections technique. The three subgroups showed identical rCBF patterns at the baseline. The MMSE score changes from the baseline at 12 months correlated significantly with rCBF changes in the frontal, parietal, temporal and limbic lobes, but not in the occipital lobe. The long-term stabilized group showed an improvement of rCBF in the widespread cerebral regions, short-term stabilized group showed no significant change, and nonstabilized group showed a decrease in several regions on quantitative CBF measurements. Frontal CBF tended to increase in the long-term and short-term stabilized groups, while parietotemporal CBF tended to decrease in the nonstabilized group. Our findings indicate that alterations in the cognitive status of AD patients receiving donepezil are paralleled by changes in the rCBF of cerebral cortices. Repeated SPECT imagings may be useful in assessing rCBF changes associated with the cognitive response to donepezil therapy, and also help to predict cognitive response after the long-term therapy.