In an attempt to improve the skin delivery characteristics of Zidovudine (AZT, azidothymidine), five aliphatic esters (acetate, butyrate, hexanoate, octanoate, and decanoate) of AZT were synthesized and assessed as prodrugs of AZT. While the water solubility of the esters is lower than that of AZT, the solubilities in isopropylmyristate (IPM) and the partition coefficients (n-octanol:buffer) are higher. Susceptibility to enzymatic hydrolysis in the rat skin homogenate increases as the acyl chain of the ester is lengthened. Among the esters, acetate (C2-AZT) and hexanoate (C6-AZT) showed 2.4- and 4.8-fold enhanced permeation in human skin from an apolar vehicle (IPM) relative to application of AZT itself, respectively.