The analytic generalized Born approximation is an efficient electrostatic model that describes molecules in solution. Here it is modified to permit a more accurate description of large macromolecules, while its established performance on small compounds is nearly unaffected. The modified model is also adapted to describe molecules with an interior dielectric constant not equal to unity. The model is tested by computations of pK shifts for a number of titratable residues in lysozyme, myoglobin, and bacteriorhodopsin. In general, except for some deeply buried residues of bacteriorhodopsin, the results show reasonable agreement with both experimental data and calculations based on numerical solution of the Poisson-Boltzmann equation. A very close agreement between the two models is obtained in an application to the prediction of the pK shifts associated with conformational change. The calculations based on this version of the generalized Born approximation are much faster than finite difference solutions of the Poisson-Boltzmann equation, which makes the present method useful for a variety of other applications where computational time is a critical factor. The model may also be integrated into molecular dynamics programs to replace explicit solvent simulations which are particularly time-consuming for large molecules.