The potential of liposome electrokinetic chromatography (LEKC), which is applied to estimate compound penetration through the skin, was evaluated in this report. Quantitative retention-activity relationships (QRARs) were successfully constructed between the compound skin permeability coefficient (log K(p)) and the retention values (log k), as well as some calculated molecular descriptors by the stepwise regression method (R(2) = 0.902). Furthermore, the developed vector method was applied to compare the similarity between the reported lipophilicity measuring scales and compounds through the skin. Both results indicated that the transport of a compound into the liposomal membrane was more similar to its penetration through the skin than that into other systems including the octanol-water system. In a word, LEKC is a promising simple method to predict drug penetration through the skin.