The exact mechanism by which anesthetics induce cell membrane-mediated modifications is still an open question. Although the fluidization effect of the anesthetic molecules on the cellular membrane is widely recognized, it is not known if anesthetics show any preference for specific membrane domains, namely the lipid rafts. The importance of these membrane micro-domains derives from the fact that they have been associated with cell signaling pathways, as well as with specific drug interactions. The objective of this work is to contribute for the elucidation of this question through the comparison of the anesthetic interactions with membranes of various lipid compositions. Liposomes prepared with an equimolar mixture of POPC, sphingomyelin and cholesterol, were chosen as models for lipid rafts. The interactions of these liposomes with two local anesthetics, tetracaine and lidocaine, and one general anesthetic, propofol, were studied. The effect of cholesterol was investigated by comparing anesthetic interactions with POPC/SM liposomes and POPC/SM/CHOL liposomes. The following experimental techniques were used: quartz crystal microbalance with dissipation, differential scanning calorimetry and phosphorus nuclear magnetic resonance. Although the liposomes investigated by the different techniques are not in the same conditions, it is possible to assemble the information obtained from all experimental techniques employed to reach a general conclusion. Tetracaine interacts more with raftlike domains, lidocaine induces stronger modifications on POPC/SM liposomes and the results for propofol are not fully conclusive but it seems to be the least prone to lipid interactions. The results were compared with those obtained with DMPC-containing liposomes, reported in a previous work.