PURPOSE: To obtain and characterize reverse hexagonal phase nanodispersions of monoolein and oleic acid, and to evaluate the ability of such system to improve the skin penetration of a model peptide (cyclosporin A, CysA) without causing skin irritation. METHODS: The nanodispersion was prepared by mixing monoolein, oleic acid, poloxamer, and water. CysA was added to the lipid mixture to obtain a final concentration of 0.6% (w/w). The nanodispersion was characterized; the skin penetration of CysA was assessed in vitro (using porcine ear skin mounted in a Franz diffusion cell) and in vivo (using hairless mice). RESULTS: The obtainment of the hexagonal phase nanodispersion was demonstrated by polarized light microscopy, cryo-TEM and small angle X-ray diffraction. Particle diameter was 181.77 +/- 1.08 nm. At 0.6%, CysA did not change the liquid crystalline structure of the particles. The nanodispersion promoted the skin penetration of CysA both in vitro and in vivo. In vitro, the maximal concentrations (after 12 h) of CysA obtained in the stratum corneum (SC) and in the epidermis without stratum corneum (E) + dermis (D) were approximately 2 fold higher when CysA was incorporated in the nanodispersion than when it was incorporated in the control formulation (olive oil). In vivo, 1.5- and 2.8-times higher concentrations were achieved in the SC and [E+D], respectively, when the nanodispersion was employed. No histopathological alterations were observed in the skin of animals treated with the nanodispersion. CONCLUSION: These results demonstrate that the hexagonal phase nanodispersion is effective in improving the topical delivery of peptides without causing skin irritation.