The antiparasitic properties of antiparasitic drugs are believed to be associated with their interactions with the protozoan membrane, encouraging research on the identification of membrane sites capable of drug binding. In this study, we investigated the interaction of mefloquine hydrochloride, known to be effective against malaria, with cell membrane models represented by Langmuir monolayers of selected lipids. It is shown that even small amounts of the drug affect the surface pressure-area isotherms as well as surface vibrational spectra of some lipid monolayers, which points to a significant interaction. The effects on the latter depend on the electrical charge of the monolayer-forming molecules, with the drug activity being particularly distinctive for negatively charged lipids. Therefore, the lipid composition of the monolayer modulates the interaction with the lipophilic drug, which may have important implications in understanding how the drug acts on specific sites of the protozoan membrane. (C) 2014 Elsevier Inc. All rights reserved.