We designed and fabricated guided-mode resonance (GMR) gratings on indium-tin-oxide (ITO) thin film to generate a significantly enhanced local electric field for surface-enhanced Raman scattering (SERS) spectroscopy. Ag nanoparticles (NPs) were self-assembled onto the surface of the grating, which can provide a large amount of “hot-spots” for SERS sensing. The ITO gratings also exhibit excellent tolerance to fabrication deviations due to the large refractive index contrast of the ITO grating. Quantitative experimental results of 5,5’-dithiobis(2-nitrobenzoic acid) (DTNB) demonstrate the best enhancement factor of ~14× on ITO gratings when compared with Ag NPs on a flat ITO film, and the limit of detection (LOD) of DTNB is as low as 10 pM.