Generalized-born surface-area (GBSA) models have proved to be effective tools for estimating rapidly and with reasonable accuracy the solvation energies of molecular and macromolecular systems, and they have been employed in conjunction with both molecular mechanical (MM) and quantum mechanical (QM) potentials. In this article, we present our work to develop a GBSA model for calculations on macromolecules using hybrid potentials in which part of the system is treated with a semiempirical QM potential and the remaining atoms with a MM potential. Our efforts have centered principally on Finding an approach for the calculation of the Born radii which is appropriate for MM and QM potentials and for small and large molecules, but inevitably, the competing requirements of these goals have meant a compromise in the design and parametrization of the model. We have. however, produced a scheme that we feet is suitable for macromolecular hybrid potential studies of processes. such as protein-ligand binding.