Ab initio (HF) and density functional theory (DFT) calculations of F-19 NMR chemical shifts were performed for models of fluoroaromatic inhibitors of carbonic anhydrase II (CA). DFT gave slightly better agreement with the experimentally measured chemical shifts of the actual inhibitors, suggesting that intramolecular dispersion does contribute significantly to the chemical shifts in these molecules. HF and DFT calculations for the stacked complex of hexafluorobenzene with benzene gave excellent agreement with experimental F-19 chemical shifts in this system. The fact that both approaches to this calculation were successful suggests that intermolecular dispersion is not an important contributor to F-19 chemical shifts in this system. Electron transfer and electrostatics must, therefore, be responsible for the changes in the F-19 NMR spectra observed on complexation. Finally, an unsuccessful attempt was made to apply HF and DFT methods to the calculation of the F-19 chemical shift of a pentafluorobenzyl-derived CA inhibitor bound to the protein in close proximity to a phenylalanine residue. A model of the inhibitor's aromatic ring interacting with the protein's aromatic residue gave a calculated chemical shift change that was much greater than that observed experimentally. Effects on the chemical shift from the field due to atoms omitted from the calculation, as well as from extensive rovibrational freedom, cannot easily be addressed in calculations of these large systems and are the likely reasons for the failure of these calculations.