Recent developments in lightweight design require an accurate fatigue assessment of welded joints. Local weld toe geometry, residual stresses and zones with varying microstructure affect the lifetime of welded structures significantly. In case of complex geometry the use of analytical stress determination is generally limited. Hence, local fatigue approaches based on numerical determination of local stresses are used widely. However, until now weld structure simulation is not entirely applied for the consideration of residual stresses within this design process. The aim of this work is on the implementation of residual stresses resulting from a weld structure simulation in a numerical lifetime assessment. In addition, local fatigue properties of characteristic microstructural zones are taken into account. The introduced simulation chain is modelled according to a two-layer submerged arc welding process. Furthermore, the main technological manufacturing procedures such as machining of the welded sheets to the final specimen geometry and stretching for residual stress homogenization are considered. In the course of the thermo-mechanical coupled weld structure simulation the software-package Sysweld is applied. Thereby the utilization of varying thermal and mechanical properties for different microstructural composition of steels and their time-temperature-transformation behaviour are included. Subsequent the numerically computed weld residual stress state is validated by X-ray measurements of the investigated submerged welded joint. Finally, a numerical lifetime assessment of the welded specimen including weld residual stresses is carried out by Femfat. Therefore the required local fatigue parameters of the base metal and characteristic microstructural zones are obtained by separate experimental fatigue tests. A concluding comparison of the numerically evaluated results with experimental fatigue test data of the welded specimen shows the significant advantages and limitations in application of the introduced methodology.