We demonstrate the use of a high refractive index waveguide structure for waveguide Raman experiments to detect thin (mono)layers of biological macromolecules on top of these waveguides. Theoretically, a combination of a thin, high refractive index layer on top of a low index substrate results in an increase in monolayer signal. A 110−130-nm-thick ZnO layer on top of a SiO2 substrate was used as a waveguide on which a very thin (8-nm) polystyrene layer could be detected with a signal-to-noise ratio (S/N) of ∼60 for a 60-s integration time. With this waveguide, Raman spectra of a monolayer of the protein bovine albumin and of a dimyristoylphosphatidylethanolamine (DMPE) Langmuir−Blodgett monolayer were measured. To our knowledge, this is the first time a waveguide Raman spectrum of a monolayer of protein is reported without resonant enhancement techniques.