In this work, an integrated simulation approach previously developed for static FE analyses is extended to microstructure- and defect-based fatigue life assessments of castings. The approach, the closed chain of simulations for cast components, combines casting process simulation with microstructure modelling and local material characterisation 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. Fatigue testing has been performed with different levels of porosities to quantify the effect of defects on the element-specific Wöhler curves. Pore characteristics are assessed using 2D X-ray, fracture surface analysis and Kitagawa diagram. The results highlight the importance of taking the risk of defect formation into consideration when designing industrial aluminium castings subjected to fatigue loads.