We hypothesised that the depletion of propylene glycol from topical formulations applied at clinically relevant doses (approximately mg/cm2) would limit its penetration enhancement effect. The in vitro percutaneous permeation of a model drug-loperamide hydrochloride-in formulations containing propylene glycol was therefore investigated under finite dose conditions. The flux of loperamide and propylene glycol across dermatomed human skin was measured. The first study examined the effect of topical loading of a gel containing 12% propylene glycol. The second study investigated the effect of propylene glycol content in creams containing 15 and 40%. Both studies showed a correlation between the amount of propylene glycol dosed on the skin and the amount of drug that had permeated. The substantial permeation of propylene glycol and relatively small permeation of loperamide, strongly suggests, that the time dependent permeation of the drug was due to the depletion of propylene glycol at the skin surface and not to the depletion of the drug itself. As often doses applied in in vitro skin permeation experiments do not match the intended clinical dosage-they are usually much greater-this study suggests that the penetration enhancement effect of propylene glycol can be overestimated in in vitro studies.