Abstract: The safety end widely exists in the primary circuit system of nuclear power plants, and its safety and reliability are crucial to the operation of nuclear power plants. In order to reduce the welding residual stress of the safety end of the reactor pressure vessel, the welding process parameters of the safety end were optimized by combining the response surface and the genetic algorithm with the factors of welding current, welding speed and interlayer cooling time. The fatigue life assessment of the safety end was also carried out based on the simulation of the in-service process. The results show that: the optimal welding process parameters for the safety end of the reactor pressure vessel are welding current 610 A, welding speed 23 mm·s^-1, interlayer cooling time 427 s; the peak welding residual stress after optimization is 373 MPa, which is 44 MPa less than that before optimization. The weakest position of the safety end is located at the center point where the first weld on the inner wall of the safe-end is welded to 90°, and the fatigue life is 4.06×10³ cycles.