We evaluated the ability of hydroxypropyl-beta-cyclodextrin (HPbetaCD) to influence the percutaneous absorption of capsaicin (CP) through isolated rat skin. Phase solubility analysis and phase distribution studies suggested the potential of HPbetaCD as a solubilizer and permeation enhancer for CP. In vitro permeation studies showed the trend that, the penetration flux (J(s)) of CP increased with the increasing concentration of HPbetaCD from 0 to 2.20% (w/v), and then decreased dramatically when the concentration of HPbetaCD kept on increasing up to 15% (w/v). 2.20% (w/v) of HPbetaCD provided both just adequate solubilization and preferred J(s) for the permeation of CP (0.075%, w/v). Similar change patterns of the permeation parameters were also observed in the hydrogels, but the J(s) of CP was reduced significantly along with the increasing concentration of Carbopol U21. Histological analysis showed an invasive action of HPbetaCD on the stratum corneum (SC) of rat skin, which could only reduce the lag time (T(L)) but could not increase the J(s) of CP. On the other hand, the complexation of HPbetaCD with CP could attenuate this invasive action. It is inferred that excess of HPbetaCD could not only disturb the percutaneous absorption of CP but also disrupt the structure of SC.