Reverse cubic and hexagonal phases of monoolein have been studied as drug delivery systems. The present study was aimed at investigating whether these systems enhance the cutaneous penetration of cyclosporin A (CysA) in vitro (using porcine ear skin) and in vivo (using hairless mice). Different mesophases were obtained depending on CysA concentration. CysA at 4% allowed the formation of reverse cubic and hexagonal phases in a temperature range of 25-40 degrees C. At 8%, CysA induced the formation of other phases, which might be due to an interaction between the polar groups of the peptide and monoolein. In vitro, the cubic phase increased the penetration of CysA in the stratum corneum (SC) and epidermis plus dermis ([E+D]) at 12 h post-application. The reverse hexagonal phase increased CysA penetration in [E+D] at 6 h and percutaneous delivery at 7.5 h post-application. In vivo, both liquid crystalline phases increased CysA skin penetration. Topical application of these systems, though, induced skin irritation after a 3-day exposure. These results demonstrate that liquid crystalline systems of monoolein are effective in optimizing the delivery of peptides to the skin. The skin irritation observed after topical application of cubic and hexagonal phases should be minimized for their safe use as topical delivery systems.