The tetrahydrogeraniol (THG) derivative, ethyl-(3,7-dimethyl octyl thio) acetate (EDOTA) was prepared by reacting tetrahydrogeranyl bromide (obtained by reaction of 40% hydrobromic acid and concentrated sulfuric acid) with ethyl 2-mercaptoacetate, while 3,7-dimethyl octyl propionate (DOP) was synthesized by a common esterification reaction by reacting THG with propionic acid in the presence of cyclohexane and concentrated sulfuric acid. The penetration-enhancing effect of the new enhancers were compared with THG and Azone in vitro using excised rat skin in modified Franz-type diffusion cells. 5-Fluorouracil (5-FU), a hydrophilic drug with poor skin permeability was used as a model permeant. Skin samples were pretreated with pure liquid enhancers for 12 h. 5-FU flux through the control and enhancer-treated skin increased linearly with its concentration in the receptor compartment. EDOTA and DOP interacted with the skin rapidly (< 2h), and the duration of action is at least 24 h. Significant differences were found in the flux values of 5-FU; EDOTA and DOP enhanced the permeability of the drug about 6-fold and 11-fold respectively. Increased partition coefficient and diffusion coefficient values were obtained by these enhancers. The results suggested that the amount of EDOTA and DOP in the skin, especially in the stratum corneum, may be related to their penetration-enhancing effect.