The exact mechanism by which anesthetics induce membrane-mediated modifications that lead to loss of sensation is still an open question. Since lipid rafts are membrane microdomains that have been associated with cell signaling pathways, as well as specific interaction with drugs, they may contribute to that mechanism. The interactions of a canonical liposomal lipid raft model, as well as of a model without cholesterol, with the anesthetics tetracaine (TTC), lidocaine (LDC) and propofol (PPF) were studied using quartz crystal microbalance with dissipation (QCM-D), differential scanning calorimetry (DSC) and phosphorus nuclear magnetic resonance (P-NMR). The three anesthetics induced effects such as membrane flu-idization, depression of phase transition temperatures, liposome swelling and/or viscosity changes of the adsorbed liposome layers on both models. Tetracaine interacts more with raftlike domains, lidocaine induces stronger modifications on POPC/SM liposomes and the results for propofol are not fully conclusive.