A computer model of the β-chain of C4b-binding protein (C4BP) was constructed, using the backbone fold of the NMR structures of the sixteenth CP module of factor H (H16) and of a pair of modules consisting of the fifteenth and sixteenth CPs of factor H (H15-16). The characteristic hydrophobic core responsible for dictating the three-dimensional structure of the CP family is conserved in the amino acid sequence of C4BP βl, β2 and β3. The distribution of the electrostatic potential shows that the model is mainly covered by a negative contour. Interestingly, a positive area is observed in the C-terminal region of the first CP module, enclosing peptide 31-45, known to be a binding site for protein S. This observation suggests that electrostatic interactions can be of importance for the interaction of C4BP to protein S. A solvent-accessible hydrophobic patch, located nearby and involving the peptide 31-45, was also found in the model, further confirming that this area is involved in the interaction with protein S. The contribution of β-chain residues 31-45 to the affinity for protein S was studied further by means of synthetic mutant peptides. The results suggest that both electrostatic and hydrophobic interactions are important for the binding to protein S.