Doxycycline is licensed for the prophylaxis of malaria and recent research has indicated the feasibility of delivering this drug across the skin. The binding of doxycycline to keratin could influence skin permeation rates and it has been suggested that the interaction of anti-malarials with melanin may contribute to side effects, such as retinal damage. Doxycycline HCl was incubated with keratin (bovine horn), melanin (Sepia officinalis) and human epidermal samples (native and delipidised). Dose dependent binding of doxycycline to keratin and melanin was observed, and was of similar magnitude for each protein. However, the binding of doxycycline to melanin was lower by an order of magnitude relative to data previously reported for some other anti-malarials, and may indicate reduced side-effects. Doxycycline also demonstrated significantly greater affinity for native epidermal skin than for delipidised skin showing that doxycycline, a charged polar molecule, has affinity for the intercellular lipid matrix in addition to the proteinaceous domain. For native skin it was estimated that saturation would be reached at approximately 140 microg x cm(-2); for delipidised skin it was estimated to be 60 microg x cm(-2). Overall, the data suggested that the partition-diffusion steps that are involved in transcellular permeation are possible.