Lipophilic vehicles and especially nail lacquers are more appropriate for topical application on the nail than aqueous systems because of their better adhesion. This work has, therefore, studied the penetration through the human nail plate of the model compound chloramphenicol from the lipophilic vehicles medium chain triglycerides and n-octanol and from a lacquer based on quaternary poly(methyl methacrylates) (Eudragit RL). The results were compared with data obtained with a keratin membrane from bovine hooves. If the swelling of the nail plate or the hoof membrane is not altered by use of lipophilic vehicles, the maximum flux of the drug is independent of its solubility in the vehicle and is the same as that from a saturated aqueous solution. These vehicles are not able to enter the hydrophilic keratin membrane because of their non-polar character and so cannot change the solubility of the penetrating substance in the barrier. If the concentration of the drug in the nail lacquer is sufficiently high, the maximum flux through both barriers equals that from aqueous vehicles or even exceeds it because of the formation of a supersaturated system. Penetration through the nail plate follows first order kinetics after a lag-time of 400 h. The course of penetration through the hoof membrane is initially membrane-controlled and later becomes a matrix-controlled process because of the membrane's greater permeability. Chloramphenicol is dissolved in the lacquer up to a concentration of 31%. The relative release rates from these solution matrices are independent of the drug concentration but they decrease on changing to a suspension matrix. These results show that drug flux is independent of the character of the vehicle and that penetration of the drug is initially membrane-controlled and changes to being matrix-controlled as the drug content of the lacquer decreases.