AMBER force fields 50 embrace two popular methods for deriving partial electrostatic charges for ligands, namely RESP 51 and AM1-BCC. The former involves a restrained fit to an electrostatic potential calculated with quantum mechanical (QM) methods, while the latter is a cheaper method based on semiempirical calculations and bond charge corrections. AM1-BCC charges are generally expected to provide values closely mimicking the RESP charges calculated at the Hartree-Fock/6-31G* level of theory but can be obtained much faster. However, differences have been reported between results emanating from the two charge systems albeit using only a small dataset with no clear conclusion as to which should be preferred. Here, we perform a comparison on a statistically significant dataset and report robust and conclusive findings.