The influence of urea on the percutaneous permeation under different conditions of application and on the epidermal effectiveness of 5-fluorouracil (FU) as an example for water-soluble agents is reported. The proceedings of permeation of FU are accelerated by admixture of, or pretreatment with, urea and by increasing the hydration of the horny layer by pretreatment with NaCl. The effectiveness of FU on the epidermis is increased simultaneously. However, the permeation rate of FU is decreased by pretreatment with HTH® as an example of a stabilized urea emulsion; on the other hand, the most favourable therapeutic effect is demonstrable. Therefore, the permeation of an agent may be both enhanced and inhibited by different modes of urea application. These findings appear to be important for both the optimization of topical treatment and the industrial medicine’s point of vi