Floating production storage and offloading (FPSO) units are important to deep-water engineering. However, the welding of some important joints of the units induces significant residual stresses, which could be released under external loading, with significant safety implications. Firstly, the residual stress and its release under loading were measured by a non-destructive X-ray method, and also simulated with the thermal elastic-plastic theory. Then, the effect of residual stress and its release on fatigue life of the welded joint was tested with a designed experimental setup and simulated with S–N curve method. The experimental and simulation results were found to be essentially consistent. The consideration of the residual stresses in a typical welded joint significantly decreased the fatigue life. Hence, for service safety, the residual stresses should always be considered in the analysis of the fatigue life of a welded FPSO structure.