Recently we have proved that Span 20 has the same enhancer effect as Azone on in vitro percutaneous penetration of lipophilic compounds (logP(oct) from 1.34 to 2.33). The purpose of this work is to study the interactions of Span 20 with stratum corneum lipids monolayers and to compare them with Azone. The surface pressure-area characteristics of Span 20 in mixed monolayers with different model lipids (ceramides, cholesterol, free fatty acids and two mixtures of ceramides+cholesterol, and ceramides+cholesterol+free fatty acids) in similar proportions to that which exists in human stratum corneum lipids were recorded as compression isotherms at 25 degrees C. Azone was also investigated on monomolecular films of some of these lipids. The results indicate that the effect exerted upon lipid packing by the Span 20 correspond, as in the case of Azone, to increased fluidity within monolayers. To quantify and compare the effect of Span 20 and Azone, the compressibility of enhancer-lipid model mixed monolayers was calculated, and expressed as a function of mole fraction of enhancer present on the films. Statistical comparison of the results obtained from both enhancers shows that they are equally potent in their interaction with the lipid models assayed. These models, if restricted, seem to be good for predict the activity and potency of percutaneous enhancers on the fluididity of the lipidic structure of the stratum corneum.