In this paper, the authors apply the ASME Boiler & Pressure Vessel Code to the structural assessment and design optimization of dissimilar welded joints subjected to transitory thermo-mechanical loads. The verification is based on the finite element stress linearization methodology. A large number of dissimilar P22/P91 steel welded joints of a power generation plant are taken into consideration. The joints vary in geometrical and operational conditions. In comparison with experimental investigations on some damaged structures, the methodology proves to be feasible, easily implemented, and reliable. Further, a second relevant result is obtained using the validated method to perform an optimization of the geometry of the joints for a safer design.