The ability of anionic surfactants, such as sodium dodecyl sulfate (SDS), to solubilize the water-insoluble protein zein in aqueous solution, referred to as the zein solubilization test, has been utilized in the past to rank the skin irritation potential and protein denaturation potential of these surfactants. With this in mind, the effects of the concentrations of SDS and of zein on zein solubilization were investigated. The behavior of the SDS-zein solutions was analyzed using a mass-balance approach that suggests that the solubilization of the zein protein induced by SDS occurs at the onset of cooperative binding of SDS to the zein protein. On the basis of the relative amounts of SDS bound to solid (undissolved) and dissolved zein, it is proposed that zein solubilization occurs when SDS denatures the solid zein protein. The effect of adding the nonionic surfactants dodecyl n(ethylene oxide) (C12En) (n = 4, 6, and 8) to SDS solutions on the interactions between SDS and zein was also investigated. The addition of the C12En surfactants led to a decrease in the ability of SDS to solubilize zein, with the greatest decrease occurring for C12E8 and the smallest decrease occurring for C12E4. The reduced ability of SDS to solubilize zein in the presence of the C12En surfactants was analyzed using a molecular-thermodynamic theory of polymer-surfactant complexation. This analysis suggests that as the head size (determined by n) or the concentration of the C12En nonionic surfactant increases, there is an increase in the steric repulsions between the zein protein and the SDS/C12En mixed micelles that complex with zein. This increased repulsion, in turn, reduces the driving force to form a cooperatively bound surfactant-protein complex and leads to a reduction in the zein solubilization capacity of the surfactant solution. Our findings can be utilized to design surfactant solutions that are less irritating to the skin through their reduced ability to solubilize zein. Moreover, implementing our findings to protein-surfactant interactions in general, they indicate that the ability of a surfactant to denature proteins can be tailored through the appropriate mixing with other surfactants, leading to a useful way to design surfactant systems that are less denaturing to proteins.