In contrast to oral administration, topical ciclosporin is not effective in the treatment of psoriasis. This may be due to the drug’s inability to penetrate the stratum corneum or to a need for systemic metabolism of ciclosporin to active metabolites. We conducted a preliminary evaluation of the ability of ciclosporin, in a variety of vehicles, to penetrate excised human skin in a two-compartment diffusion cell, a standard in vitro technique for evaluating percutaneous drug delivery. A high-pressure liquid chromatography assay for ciclosporin did not detect the passage of ciclosporin through skin. This finding was consistent through multiple trials, some of which evaluated Azone or liposomal formulations, which are reported to enhance the penetrability of certain compounds. These results indicate that ciclosporin is unable to penetrate human skin in the vehicles tested. This may explain the lack of clinical efficacy we demonstrated in 5 patients with psoriasis treated with topical ciclosporin for 14–16 days.