Presence of specific receptors for volatile anesthetics has recently been proposed (Evers, A.S. et al. (1987) Nature 328, 157-160) by a finding that halothane uptake by the rat brain was characterized, in part, by saturable binding. We report here that volatile anesthetics bind model lipid membranes also with saturable and unsaturable kinetics. Binding of enflurane to dipalmitoylphosphatidylcholine vesicle membranes was measured by gas chromatography. At low anesthetic concentrations, comparable to the clinical level, the interaction was saturable. After reaching a temporary saturation, a sudden increase in the anesthetic binding to the membrane occurred, when the anesthetic concentration in the aqueous phase exceeded 2.7 mM, or 6.3 x 10(-2) atm partial pressure in the gas phase in equilibrium with the aqueous phase. The secondary binding was linear to the aqueous anesthetic concentrations and was unsaturable to the limit of this study. We also found that enflurane self-aggregated in water above 4 mM. When the aqueous concentration exceeded 6 mM, the aggregation number was about 8. We conclude that the saturable binding indicates adsorption onto the vesicle surface, and the unsaturable binding indicates multilayer stacking of the enflurane molecules, where the initially adsorbed molecules provide the binding sites to the succeeding molecules according to the multilayer condensation kinetics. The tendency of enflurane to self-aggregate in water promotes the multilayer stacking at the surface of the membrane.