The purpose of this study was to investigate the effects of various solvent systems containing water, ethanol, propylene glycol (PG), and their binary combinations on the ex vivo permeation of zidovudine (AZT) across Sprague-Dawley rat skin using Franz diffusion cells at 37 degrees C. Further, saturation solubility and epidermis/vehicle partition coefficient of AZT in the solvent systems, and their effect on percentage hydration of epidermis using thermogravimetric analysis were determined to understand the mechanisms by which these solvent systems change drug permeability properties. All binary combinations of PG, ethanol and water significantly increased saturation solubility of AZT. Maximum AZT flux was observed with 66.6% ethanol among ethanol-water solvents, with 33.3% PG in PG-water solvents and with 100% ethanol among PG-ethanol combinations. PG-water and PG-ethanol solvents neither reduced the lag time nor increased AZT flux across rat skin. In addition, high concentrations of PG in both water and ethanol reduced steady state flux of AZT. Further, thermogravimetric studies revealed that solvents containing high PG concentrations dehydrate epidermis. Among all the solvent combinations, highest flux and short lag time were achieved with ethanol at 66.6% in water and hence is a suitable vehicle for transdermal delivery of AZT.