Vacuum induction melting technology is an important method for producing high-quality titanium alloy. The key challenge lies in the development of refractories with excellent chemical stability for titanium alloy corrosion. In this work, CaO-Al2O3-TiO2 refractories are proposed as the potential materials for Ti6Al4V alloy smelting. Four CaO-Al2O3-TiO2 refractories with different TiO2 contents were prepared and their reaction behaviours in contact with titanium aluminum melts were investigated in detail. When the refractory has a suitable content of CaTiO3 phase, it promotes the diffusion and mass transfer rate of ions and improves the sintering reaction activity, leading to good high temperature mechanical properties and corrosion resistance to titanium aluminum alloy. However, when the TiO2 component is excessive, CA6 has been completely wrapped by CaTiO3, and some CA6 grows abnormally, resulting in a decrease in high temperature mechanical properties of the refractory. Moreover, during the smelting of Ti6Al4V alloy, Al component reacts with CaTiO3 to produce metallic Ti and calcium aluminate phase with low melting point, resulting in degradation of refractory.