Abstract: OBJECTIVE To investigate the transdermal properties of terbinafine hydrochloride in vitro, explore the interactions between terbinafine hydrochloride and skin, and clarify the mechanism of the transdermal properties of terbinafine hydrochloride based on drug-skin interactions. METHODS Drug transdermal penetration, intradermal retention, and distribution in various layers of the skin had been compared. Drug-skin interactions had been studied with ATR-FTIR, DSC and Raman spectra, and the interactions between keratin, lipids of stratum corneum(SC) and drug were simulated and calculated in the computer. RESULTS Terbinafine hydrochloride exhibited high skin retention and low penetration. The retained drugs were mostly distributed in the SC. It could interact with both the lipids and keratin in the SC. These interactions made transdermal process difficult and caused great penetration variation. CONCLUSION The interaction of terbinafine hydrochloride with skin lipids and proteins is one of the mechanisms by which it exhibits typical high skin retention skin and low permeability. It provides a theoretical basis for the transdermal properties of high retention and low permeability of terbinafine hydrochloride in vitro.