A series of 1-benzyl-4-[2-(N-benzoylamino)ethyl]piperidine derivatives and of N-benzylpiperidine benzisoxazoles has been investigated using the comparative molecular field analysis (CoMFA) approach. These compounds have been found to inhibit the metabolic breakdown of the neurotransmitter acetylcholine (ACh) by the enzyme acetylcholinesterase (AChE) and hence alleviate memory deficits in patients with Alzheimer's Disease by potentiating cholinergic transmission. Development of the CoMFA model considered two separate alignments: (i) alignment I which emphasized the electrostatic fitting of the subject compounds and (ii) alignment II which emphasized their steric fitting. In addition, the inhibitor compounds were considered both as neutral species and as N-piperidine-protonated species. The resulting 3D-QSAR indicates a strong correlation between the inhibitory activity of these N-benzylpiperidines and the steric and electronic factors which modulate their biochemical activity. A CoMFA model with considerable predictive ability was obtained.