Mycophenolate mofetil, the morpholinoethylester of mycophenolic acid, is an immunosuppressant used in combination with ciclosporin (cyclosporin) and corticosteroids to prevent organ rejection after heart and kidney transplantations. The drug seems also to be effective in dermal diseases after systemic administration. However, up to date mycophenolate mofetil can be only systemically administered and this is associated with several side effects such as nausea, leucopenia, sepsis, and diarrhoea. The aim of this study was to develop a topical formulation containing mycophenolate mofetil and to investigate in-vitro release and penetration into human skin ex-vivo. HPLC was applied to quantify mycophenolate mofetil after release studies from semisolid formulations using a dodecanol-collodion membrane as a lipophilic acceptor. Penetration studies with an amphiphilic cream using excised human breast skin were carried out in Franz-type diffusion cells. Mycophenolate mofetil and its active metabolite mycophenolic acid were detected by HPLC-MS after microsectioning in different skin layers. In this study the penetration of mycophenolate mofetil from an amphiphilic cream into excised human skin was shown. Additionally, the enzymatic hydrolysis of penetrated mycophenolate mofetil into mycophenolic acid was proven even under ex-vivo conditions. In-vivo a higher extent of metabolism of mycophenolate mofetil to mycophenolic acid would be expected because of the complete enzyme activity. This topical formulation might be a promising alternative to the usual systemic administration of mycophenolate mofetil in the treatment of skin diseases such as psoriasis.