Abstract: The electron beam welding process of 130 mm thick damage tolerance TC4-DT titanium alloy was studied by orthogonal experiment with four factors and four levels, and the process parameters with good cross-sectional shape of the joint were found. The significance of the influence of various welding parameters on the weld penetration depth was analyzed. The results show that, the acceleration voltage has the greatest impact on the weld penetration of the joint, while the beam intensity has the smallest impact on the weld penetration. The optimal process parameters in the orthogonal experiment were used for welding, and then the layered microstructure and mechanical properties of the electron beam welded joints under these parameters were compared. The 15-35 mm area from the upper surface of the workpiece is the first layer, the 55-75 mm area is the second layer, and the 95-115 mm area is the third layer. The results show that there is little difference in the microstructure of each layer of the joint, in which the acicular martensite α' phase in the first layer is less, the average microhardness in the first layer is smaller, and the difference in microhardness in the other layers is not obvious. The microstructure of each weld zone contains acicular α' phase, and its strength is higher than that of the base metal. The tensile test of each layer of the joint is broken in the base metal, and a large number of dimples are found in the fracture of each layer of the weld zone. The elongation of each layer of the joint has little difference, which is lower than that of the base metal. Compared with the base metal, the α phase in the joint is less, the slip deformation is difficult, the prescribed plastic strength of the joint is higher than that of the base metal, and the specified plastic, strength values of the joint and each layer of the base metal are close respectively.