The quartz crystal microbalance (QCM) is increasingly used for monitoring the interfacial interaction between surfaces and macromolecules such as biomaterials, polymers, and metals. Recent QCM applications deal with several types of liquids with various viscous macromolecule compounds, which behave differently from Newtonian liquids. To properly monitor such interactions, it is crucial to understand the influence of the non-Newtonian fluid on the QCM measurement response. As a quantitative indicator of non-Newtonian behavior, we used the quartz resonator signature, S2 , of the QCM measurement response, which has a consistent value for Newtonian fluids. We then modified De Kee’s non-Newtonian three-parameter model to apply it to our prediction of S2 values for non-Newtonian liquids. As a model, we chose polyethylene glycol (PEG400) with the titration of its volume concentration in deionized water. As the volume concentration of PEG400 increased, the S2 value decreased, confirming that the modified De Kee’s three-parameter model can predict the change in S2 value. Collectively, the findings presented herein enable the application of the quartz resonator signature, S2 , to verify QCM measurement analysis in relation to a wide range of experimental subjects that may exhibit non-Newtonian behavior, including polymers and biomaterials.