A computational methodology for pK(a) predictions of small molecules based on an ab initio quantum mechanics (QM) description of the acid and a linearized Poisson-Boltzmann equation (LPBE) description of bulk solvation using the polarized continuum method is presented. This QM/LPBE method is capable of reproducing the pK(a)'s of several functional groups found in amino acid residues with a rant-mean-square deviation from experiment of 0.6 pH units. The practical applicability of the QM/LPBE method is extended to proteins by using a QM description of the ionizable residue and an effective fragment potential (MM) description of the rest of the protein. This QM/MM/LPBE method is used to predict a pK(a) of the Lys55 residue in turkey ovomucoid third domain of 11.0, which is in good agreement with the experimental value of 11.1.