Using silica sol as a binder for titanium investment casting is very attractive due to its good stability and reasonable cost as compared with yttrium sol and zirconium sol. However, the mechanism of interface reaction in the related system remains unclear. In this investigation, the interface reaction between Y2O3-SiO2 (Y-Si) shell mold and titanium alloys was studied. A group of shell molds were prepared by using Y2O3 sand and silica sol with different contents of SiO2. Ti-6Al-4V alloy was cast under vacuum by gravity casting through cold crucible induction melting (CCIM) method. Scanning electron microscopy (SEM) and energy dispersive x-ray spectroscopy (EDS) were employed to characterize the micromorphology and composition of the reaction area, respectively. X-ray photoelectron spectroscopy (XPS) was used to confirm the valence state of relevant elements. White light interferometer (WLI) was used to obtain the surface topography of Y-Si shells. The results show that the thickness of reaction layers is below 3 μm when the SiO2 content of silica sol is below 20wt.%. Whereas, when the SiO2 content increases to 25wt.%, the thickness of the reaction layer increases sharply to about 15 μm. There is a good balance between chemical inertness and mechanical performance when the SiO2 content is between 15 and 20wt.%. Moreover, it was found that the distribution of SiO2 and the roughness at the surface of the shell are the key factors that determine the level of reaction.