Poly (acrylic acid) gels containing 5-fluorouracil (5-FU) and Azone were prepared and the effects of Azone on 5-FU release from the gels and on 5-FU permeation across the skin were studied by in vitro and in vitro methods. 5-FU was released rapidly from the gels. The release rate of 5-FU from the gels was higher than that from a commercial ointment. Azone did not affect the in vitro drug release from the gels. Experiments on in vitro permeation of 5-FU across the hairless rat skin with vertical diffusion cells showed that addition of Azone to the gels markedly enhanced the 5-FU permeability, although a lag time of approximately 6 h was observed. Increasing the Azone concentration in the gels to 15% proportionally increased the permeability of 5-FU. More than 10 h was required to reach a steady-state blood level of 5-FU after administration of 5-FU-Azone gel topically. Pretreatment with Azone, however, shortened the lag time so that a steady-state level was reached sooner. The area under the blood concentration-time curve (AUC) after topical administration was comparable to that after oral administration. These results suggest not only that Azone would be very useful for increasing the skin permeability and blood level of 5-FU, but also that Azone might be useful for developing transdermal therapeutic systems for the delivery of practically unabsorbable drugs.