A QSAR study was performed in an attempt to explore the pharmacophore of some benzodiazepine derivatives as anti-Alzheimer agents for the inhibition of gamma-secretase. The study, which used the electrotopological state atom (ETSA) index, which encodes electronic and topological information, reveals the importance of two phenyl rings-one substituted and another unsubstituted, for the inhibition of the enzyme. Fluorine substitution on the substituted phenyl ring has an important contribution to the activity. R-configurations of the aliphatic chain substituents provide the exact conformation of the molecules to enter into the binding pockets of the receptor(s). [figure: see text]. General structure of benzodiazepine containing gamma-secretase inhibitors.