Further development of an approach for representing, efficiently calculating and comparing discreet 3-dimensional molecular electrostatic potentials using a quantitative similarity index (MEP-SI) based on the Carbo formalism is presented. A radial-type (MACRA) grid representation is described which provides: much more efficient storage of MEP information than a cubic grid of similar range; appropriate emphasis; and a convenient means for restricting the comparison of MEP functions to a local molecule region. The MACRA based MEP-SI formalism was used to evaluate the suitability of a variety of approximate methods for efficiently calculating the MEP for use in MEP-SI comparison of dissimilar molecules. The Mulliken charge method did not produce MEP functions of sufficient accuracy, particularly for molecules with flat, non-polar MEP functions or with large polar atoms, such as sulfur. The method of potential-derived charges (PDC's), with additional charges for lone pair electrons included on sulfur, provided an efficient and sufficiently accurate representation of the MEP for this purpose. Convergence of the MEP-SI with respect to MACRA grid extent and point density was demonstrated, and the effect of the different grid point emphasis in the MACRA versus the cubic grid representation was investigated. Finally, the alternative similarity index formula suggested by Hodgkin et al. did not produce results appreciably different from the Carbo formula when PDC's, rather than Mulliken charges, were used to generate MEP functions.