A simple algorithm for the calculation of multiple site titration curves is proposed. It is based on a hybridization of two computational techniques: (i) a modified Tanford-Roxby iterative procedure [Tanford and Roxby (1972) Biochemistry, 11, 2193-2198] and (ii) the Boltzmann statistics. The sites characterized by strong electrostatic coupling were selected for statistical mechanical treatment, whereas all other sites were treated by means of the modified Tanford-Roxby procedure. The selection of the two sets was made on the basis of a criterion related to the interaction energy between the titratable sites in the protein molecule. The algorithm was tested for bovine pancreatic trypsin inhibitor and the pK values calculated were discussed in the light of experimental data and theoretical results obtained by other authors. The algorithm can easily be coded and incorporated into any program package for the calculation of electrostatic interactions in proteins.