Department of Chemistry and Supercomputing Institute, University of Minnesota, 207 Pleasant Street S.E., Minneapolis, Minnesota 55455-0431Abstract: We present a new self-consistent reaction field continuum solvation model based on the generalized Born (GB) approximation for the bulk electrostatic contribution to the free energy of solvation. The new model improves on the earlier SM8 model by using the asymmetric descreening algorithm of Grycuk to treat dielectric descreening effects rather than the Coulomb field approximation; it will be called Solvation Model 8 with asymmetric descreening (SM8AD). The SM8AD model is applicable to any charged or uncharged solute in any solvent or liquid medium for which a few key descriptors are known, in particular dielectric constant, refractive index, bulk surface tension, and acidity and basicity parameters. It does not require the user to assign molecular mechanics types to an atom or a group; all parameters are unique and continuous functions of geometry. This model employs a single set of parameters (solvent aciditydependent intrinsic Coulomb radii for the treatment of bulk electrostatics and solvent descriptiondependent atomic surface tensions coefficients for the treatment of nonelectrostatic and shortrange electrostatic effects). The SM8AD model was optimized over 26 combinations of theoretical levels including various basis sets (MIDI!, 6-31G*, 6-31+G*, 6-31+G**, 6-31G**, cc-pVDZ, DZVP, 6-31B*) and electronic structure methods (M05-2X, M05, M06-2X, M06, M06-HF, M06-L, mPW1PW, mPWPW, B3LYP, HF). It may be used with confidence with any level of electronic structure theory as long as self-consistently polarized Charge Model 4 or other self-consistently polarized charges compatible with CM4 charges are used, for example, CM4M charges can be used. With M05-2X/6-31G*, the SM8AD model achieves a mean unsigned error of 0.6 kcal/mol on average over 2 560 solvation free energies of tested aqueous and nonaqueous neutral solutes and a mean unsigned error of 3.9 kcal/mol on average over 332 solvation free energies of aqueous and nonaqueous ions.