The adsorption of lipid vesicles on a;hydrophobic substrate has been investigated in aqueous buffer solution by means of the quartz crystal microbalance (QCM) and ellipsometry. As a hydrophobic substrate, 1-octadecanethiol (ODT) was self-assembled on a gold-coated AT-cut quartz, and lipid vesicles were prepared by the injection method using the synthetic phospholipid L-alpha -dipalmitoylphosphatidylcholine (DPPC). Although the in-situ ellipsometry thickness measurement dictated that only a monolayered DPPC was formed on the ODT-modified gold substrate, the frequency change measured by QCM was found to correspond to the formation of nearly 30 layers of DPPC on ODT when the usual Sauerbrey equation was assumed to hold in the present system as well. To interpret the nonideal QCM behavior, we have developed a modified four-layer model for QCM operating in a liquid medium. On the basis of the model, the physical characteristics of QCM were related to the electrical parameters of the equivalent QCM circuit. The proper values of the electrical parameters determined from a separate impedance analysis were then used to evaluate the physical properties of the electrode-adjacent liquid layer. It thus appeared that the unusual response of QCM was caused by the much larger viscosity of the electrode-adjacent liquid layer rather than that of the bulk phase. This in turn is presumed due to vesicles being intact on the planar DPPC layer assembled on ODT.