In this work, “the closed chain of simulations for cast components”, previously developed for static FE analyses, is extended to microstructure- and defect-based fatigue life assessments of castings. The approach combines casting process simulation with microstructure modelling and local material characterization to generate heterogeneous material data for FE analysis and fatigue life assessment. The method is demonstrated on a High-Pressure Die Cast aluminium component. Areas with a high risk of defects are identified based on the simulated solidification conditions, and heterogeneous material data for the fatigue life analysis is generated. To quantify the effect of defects on the element-specific Wöhler-curves, fatigue testing has been performed with different levels of porosities characterized by x-ray, fracture surface analysis and Kitagawa-diagram. The results highlight the importance of taking the effect of the casting process, in terms of microstructure, defects and residual stresses, into consideration to predict the fatigue life of industrial aluminium castings correctly.