One of the most important lessons that can be learned from studies of protein-surfactant interaction is that the details of the process reflect the detailed tertiary structures of the proteins. The binding of ionic surfactants to different water-soluble proteins; urease, peroxidase, human serum albumin and amino acid oxidase, were extensively studied by equilibrium dialysis and isothermal titration microcalorimetry techniques. The electrostatic interaction, which is accompanied by a preliminary hydrophobic interaction, occurs initially and is followed by a more extensive pure hydrophobic interaction The predominant unfolding of a protein is related to the first interaction, in which neutralization of charges at the surface of the protein perturb the balance of forces in the protein structure. The number of binding sited in the first set gl, is markedly consistent with concentration at midpoint of denaturation profiles and very close to the sites at the surface of the single subunit protein with opposite charge with respect to the ionic head group of surfactant.