The interaction of the fluorinated benzyl ring of a series of inhibitors of carbonic anhydrase II (CAII), fluorine-substituted N-(4-sulfamylbenzoyl)benzylamines (SBB), with nearby residues in the active site has been studied using a hybrid QM/MM model. To account for the important dispersive interactions between the fluorinated benzenes and these residues, a density functional method with an empirical dispersive term, (DFT-D), is used as the QM part of the model. The major interactions are found to be between the substituted benzenes and the aromatic ring of a nearby phenylalanine residue. However, the intermolecular separations between these two groups span a greater range than that found for comparable interactions between isolated molecules, showing the importance of interactions with other residues, which have been quantified. A decomposition of the interaction energy between the fluorobenzenes and each residue has been carried out which shows the dispersive interactions to be dominant. This work has shown that a QM(DFT-D)/MM model is a computationally feasible and accurate way of studying substrate–protein interactions.