A generalized Born/surface area (GB/SA) water model (Qiu, D.; Shenkin, P. S.; Hollinger, F. P.; Still, W. C. J. Phys. Chem. A 1997, 101, 3005-3014) in combination with the GROMOS96 force field is parametrized with the specific goal of application to protein simulations. The parameters are determined by a combined procedure of fitting to the free energies of solvation of amino acid-mimicking small molecules, rationally considering the effects of the solvent model on hydrogen-bond interactions, and most critically, carrying out long-time trial molecular dynamics simulations on two structurally distinct proteins, the B I domain of streptococcal protein G and the bovine pancreatic trypsin inhibitor. The refined set of parameters is tested by carrying out a simulation on a third protein, the chymotrysin inhibitor 2. For all three proteins, we report separate 3 ns simulations using, respectively, the re-parametrized GB/SA model, the explicit solvent model, and another implicit solvent model which is mainly based on the solvent-accessible surface area. The simulations with the GB/SA model show excellent agreement with crystal structures and explicit solvent simulations. The root-mean-square error of the final GB/SA model in the free energies of solvation for 16 amino acid analogues is 1.12 kcal/mol. We believe that the procedure of considering structurally distinct proteins in parametrization and running final tests on unrelated proteins is essential for avoiding biasing the model toward stabilizing certain types of protein structures. The results indicate that the model can be widely used in future studies of protein conformations and dynamics.