Considering the crystallographic data of the Human HMG-CoA reductase (HMGR) complexed with statins, a quantum chemistry study, based on the density functional theory, is performed to estimate the interaction energy for each statin, when one considers binding pockets of different sizes, based solely on the interpretation of crystallographic data of the HMGR–statin complex. Assuming a correlation between the statin potency and the strength of the HMGR–statin binding energies, clinical data of these cholesterol-lowering drugs are successfully explained after stabilization of the calculated binding energy for a larger size of the ligand-interacting HMGR region. The statins atorvastatin and rosuvastatin are shown to be the most strongly bound HMGR inhibitors, while simvastatin and fluvastatin are the weakest ones. An accurate description of the residue–ligand interaction energies at the binding site suggests a quantum chemistry–based route for the development of new statin derivatives.