Although clinical and experimental research has demonstrated that acetylcholinesterase inhibitors, such as donepezil, are able to enhance cognitive functioning in intact subjects as well as in patients affected by different degrees of dementia, no morphological study has ever analyzed whether donepezil treatment is able to modify neocortical neuronal morphology in the intact brain and in response to cholinergic depletion. Spines (number, density, distribution) and branching (length, intersections, nodes) of apical and basal dendrites of III-layer parietal pyramidal neurons were evaluated following chronic donepezil treatment in intact animals and in animals in which the cholinergic lesion was produced by intracerebroventricular injections of immunotoxin 192 IgG-saporin. In intact animals, the drug treatment provoked a proximal shift of spines towards the cell soma in basal dendrites. In lesioned animals, donepezil treatment reduced the upregulation of the spines induced by the cholinergic lesion in both apical and basal dendrites. Thus, while in the intact brain chronic donepezil treatment induced plastic changes in the dendritic morphology of pyramidal neurons of parietal cortex, in the presence of cholinergic depletion, it prevented the compensatory response of parietal pyramidal neurons to the loss of cholinergic inputs from basal forebrain.