In the cylinder heads produced by the Lost Foam Casting process, the microstructure consists of hard intermetallic phases and large gas and microshrinkage pores. In order to study the influence of this complex 3D microstructure on fatigue crack initiation and propagation, an experimental protocol using laboratory and synchrotron tomography, Finite Element simulation and 3D Digital Volume Correlation has been used. Tests performed at low temperatures (room temperature and 150°C) revealed the initiation of 3D cracks at large pores and a propagation along the hard inclusions towards the free surface. At temperatures characteristics of in-service conditions (above 200°C), an additional damage mechanism was observed: cracks were detected in silicon particles around the main pore that drove to failure but also in other areas of the specimen gauge length.