The titration behavior of the ionizable residues of the HyHEL-5-hen egg lysozyme complex and its individual components has been studied using continuum electrostatic calculations. Several residues of HyHEL-5 had pKa values shifted away from model values for isolated residues by more than three pH units. Shifts away from the model values were smaller for the residues of hen egg lysozyme. A moderate variation in the pKa values of the titratable groups was observed upon increase of the ionic strength from 0 to 100 mM, amounting to 1-2 pH units in most cases. Under physiological conditions, the net charge of HyHEL-5 was opposite that for hen egg lysozyme. Several residues, including those involved in the Arg-Glu salt bridges that have been proposed to be important in antibody-antigen binding, had pKa values that were changed significantly upon binding. The main titration event upon antibody-antigen binding appears to be loss of a proton from residue GluH50 of the Fv molecule. The limitations of our calculation methods and the role they might play in the design of antibodies for use in assays, sensors and separations are discussed.