The pH-dependent characteristics of a protein are determined by the pK(a)s of its titratable residues, Continuum electrostatic approaches provide a fast means of calculating the pK(a)s of the titratable residues in proteins immersed in aqueous ionic solution. Here, we show how optimization of the parameters used in continuum electrostatic calculations can lead to significant improvements in the accuracy of pK(a) predictions. Dependence on the protein dielectric constant is studied, and two classes of ionizable sites are identified : (1) a large number of mostly solvent exposed residues for which the best pK(a) is calculated if the protein dielectric constant is set close to that of the aqueous solvent; and (2) a small number of mostly buried residues for which the best pK(a) is calculated with a lower site-specific protein dielectric constant, These two classes of ionizable sites can be distinguished using a criterion based on desolvation energy, A priori determination of the optimum protein dielectric constant for the second class is not easy, but satisfactory results are obtained if it is assigned in the range 10-20, The accuracy of the calculated pK(a)s is influenced by the assignment of proton positions and we suggest modifications to the OPLS parameter set that eliminate the need to construct hypothetical, and therefore error prone, proton positions during the calculation procedure, For the test set of proteins studied, the final recommended protocol enables the tautomers of histidine residues to be assigned automatically, the pK(a)s of residues in the "high dielectric constant" class to be calculated to within 0.7 pK(a) units, and the pK(a)s of residues in the "low dielectric constant" class to be calculated to within 1.6 pK(a) units.