Dehydroepiandrosterone (DHEA) and its sulfate conjugate (DHEAS) are the major secretory steroidal products of the adrenal gland. Some epidemiologic studies have found an association between low DHEA serum levels in patients and many important diseases. To prevent all such pathological conditions and, in any case, in aging, a DHEA supplementation has been proposed. DHEA shows a low oral bioavailability; taking the bioavailability obtained by the subcutaneous route as 100%, it was estimated that the potencies of DHEA by the percutaneous and oral routes were approximately 33% and 3%, respectively. Thus, transdermal patches could be considered a promising formulation as a continuous and controlled delivery of DHEA in replacement therapy is desired. With the aim of evaluating the effect of the matrix composition in terms of polymers and enhancers on the DHEA skin permeation flux, 10 types of monolayer self-adhesive patches containing 0.25mg/cm2 of active ingredient were designed. The matrices were based on three different acrylic copolymers: an acrylate-vinylacetate copolymer, a polyaminomethylmethacrylate (PAMA), and a polymethylmethacrylate. Transcutol (TR), mint essential oil, Lauroglycol, Brij 58, and propylene glycol (PG) were evaluated as DHEA skin permeation enhancers. All prepared patches were characterized by drug content, light microscopy, and in vitro skin permeation, performed using a modified Franz-type diffusion cell and human stratum corneum and epidermis as a membrane. The in vitro skin permeation studies are particularly significant in the development studies of DHEA patches as the in vivo determination of DHEA is affected b the fact that the endogen substance in the plasma is not constant over time. Among the testedpatches, highest DHEA fluxes were obtained using the formulation based on PAMA. Moreover, the introduction in the matrix of binary mixtures of TR and PG, used also for their plasticizer properties, permitted enhancing DHEA skin permeation. On the basis of these studies, the transdermal administration of DHEA using patches seems feasible.