This work studied the interactions of an oppositely charged surfactant mixture of oleyl bis(2-hydroxyethyl)methyl ammonium bromide (OHAB) and sodium dodecyl sulfate (SDS) with 1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phosphocholine (DOPC) vesicles as well as the penetration of the OHAB/SDS mixture through model skin, aimed at understanding the relationship between the ability of different surfactant aggregates in solubilizing phospholipid vesicles and their potential in irritating skin. By changing the molar fraction of OHAB (X), five kinds of aggregates are constructed: OHAB and SDS separately form cationic and anionic small micelles, whereas the OHAB/SDS mixtures form cationic and anionic vesicles at X = 0.30 and 0.70, respectively, and weakly charged vesicles at X = 0.50. The mixtures have much lower critical micellar concentrations (CMCs) and much larger aggregates than either OHAB or SDS alone, and the CMC and the size of the OHAB/SDS vesicles decrease with the increase in X. The phase diagrams indicate that the OHAB/SDS mixtures show much stronger ability in solubilizing the DOPC vesicles than individual OHAB and SDS and decrease in the order of X = 0.30 > 0.50 > 0.70 ≫ 1.00 > 0. However, the ability of the surfactants in penetrating the model skin decreases reversely, and the penetration of the surfactants are significantly reduced by mixing. These results indicate that the surfactant mixture with a larger aggregate size and a smaller CMC value displays much stronger ability in solubilizing the DOPC vesicles but much weaker ability in penetrating the skin.