This study investigated the behaviour and mechanism of interfacial microstructure evolution during long term high temperature exposure and the effect of interface structure on creep failure in the dissimilar metal welds (DMWs) involving ferritic heat resistant steels with nickel-based filler metal. The welding of nickel-based and ferritic materials led to the formation of interfacial martensite layer in the ferritic steel side of DMW. During long term high temperature exposure, interfacial martensite transformed to ferrite due to C diffusion and migration in the micro-region near the BCC/FCC interface between the martensite layer and the weld metal. The martensite-ferrite transformation was attributed to the large C chemical potential gradient caused by chemical composition gradient. Under creep condition, the failure of DMW was prone to occur along the weld metal/ferritic steel interface, which was related to strain concentration around the interfacial ferrite formed during service. Hence, the relationships between interface structures before and after service and interfacial failure in the DMWs were clarified.