The percutaneous absorption of the polar drug methotrexate has been examined in vitro. Two alcoholic gel formulations containing 1% methotrexate with or without Azone® were applied to full-thickness abdominal human skin mounted in all-glass Franz-type diffusion cells. In the absence of Azone® no percutaneous penetration of methotrexate was observed. In the presence of Azone® 190 ng/cm² permeated after 48 h. Azone® appears to be actingas an efficient penetration enhancer for this drug.