The effects of anesthetic drugs on lipid order were evaluated by the fluorescence polarization of the probe molecule, 1,6-diphenyl-1,3,5-hexatriene (DPH) incorporated into vesicles of dimyristoyl-phosphatidylcholine (DMPC) and DMPC with 10 mol% ganglioside (GDL2). Anesthetics (enflurane, chloroform, diethylether, pentobarbital, ethanol, butanol, hexanol) decreased the fluorescence polarization of DPH in vesicles of DMPC, but relatively large concentrations were required. Addition of gangliosides to DMPC enhanced the lipid disordering effects of anesthetics by several fold. The potencies of these anesthetics in decreasing fluorescence polarization of DPH in DMPC-ganglioside was well correlated with their potencies as anesthetics, and significant decreases in fluorescence polarization occurred at pharmacologically relevant concentrations. These results indicte that gangliosides can enhance the sensitivity of membrane lipids to the disordering effects of anesthetics and suggest that the large ganglioside content of the outer leaflet of the lipid bilayer of neuronal membranes may render this membrane region unusually sensitive to anesthetic agents.