Pipeline transmission is an essential means of oil and gas transportation, but its safety is threatened by fatigue fracture that generally occurs in the heat-affected zone (HAZ) adjacent to welded joints of the pipeline. Therefore, it is important to determine the fatigue properties of HAZ. In this work, the microstructure and mechanical properties in the HAZ of a X80 pipe were accurately simulated by thermal simulation. The fatigue life and crack growth rate of typical sub-HAZ were tested. The results showed that fine grain HAZ exhibited the lowest strength and fatigue life. In contrast, coarse grain HAZ had the highest strength, but its fatigue life was lower than that of the intercritical HAZ. The microstructure of each sub-HAZ and the effect of this structure on fatigue properties were analysed and discussed in detail. The results provide insight into the effects of microstructure and mechanical properties on the service safety of pipeline transportation.