Cytochrome c oxidase is a redox-driven proton pump that converts atmospheric oxygen to water and couples the oxygen reduction reaction to the creation of a membrane proton gradient. The structure of the enzyme has been solved; however, the mechanism of proton pumping is still poorly understood. Recent electrostatic calculations of this group indicate that one of the histidine ligands of enzyme's CUB center, His291, may play the role of the pumping element. In the present paper, we use first principles to study models of the catalytic center of CcO, and calculate the pK(a) of the His291 residue for both the reduced and oxidized states of the Cu-B center. We used density functional theory to calculate the proton affinity of the sigma-nitrogen of His291, and we used the self-consistent reaction field method to calculate the solvation energies. The pK(a) of 4-methylimidazole was calculated first to establish the accuracy of our method. For the reaction center, two different models were used. The minimal model contains only the Cu-B center, its histidine ligands, and a water ligand. The extended model consists of the iron porphyrin (ferryloxy state) of Heme alpha(3), and its axial histidine, in addition to the Cu-B complex. Using the minimal model, we obtained aqueous phase pK(a)'s for the His291 residue of 9 and 13, with oxidized and reduced CUB respectively. The pK(a)'s are 6.3 and 14.5 using the extended model. When the dielectric constant is set to is an element of = 4 to reflect protein environment, the pK(a) with oxidized Cu-B drops to -4.8, whereas with reduced Cu-B it increases slightly to 15.7.