This study evaluates the thermal structural safety of the three-way catalyst(TWC) substrate for domestic passenger cars. Thermal-fluid boundary conditions on the TWC substrate were determined by D-optimal DOE. The thermal stresses on the TWC substrate were calculated by the temperature distribution obtained from the CFD results. The safety factors of the TWC substrate were determined by statistical strength and stress distributions and estimated to be 0.275. The thermal stresses for TWC substrate exceeded the strength of the material. Therefore, it is necessary to redesign the TWC substrate because it has much shorter service life than design life.