High-pressure die-cast (HPDC) components are being increasingly used due to good flexibility and high productivity. These aspects make HPDC suitable to produce several mass components, especially for the automotive sector. Due to the rapid filling of the die and high cooling rate, the process generally leads to the formation of a wide variety of defects, such as porosity and oxide films. Such defects might act as starting points for fatigue cracks and thus deteriorating the fatigue behavior of the casting. To this respect, the fatigue behavior of die cast aluminum alloys is an important aspect to consider when assessing the performance of complex castings for automotive applications. In the light of these aspects, the goal of this work is to describe how the microstructure affects the fatigue crack initiation and propagation. Die cast AlSi9Cu3(Fe) specimens were produced by means of a specifically designed die and the microstructure was preliminary characterized. Uniaxial fatigue tests were performed at load control with a stress ratio of R = 0.1 and at a single level of stress amplitude. After the fatigue tests, the samples were investigated to assess the propagation of the fatigue cracks; the starting points of cracks were specifically identified and the obtained data suggested how defects strongly influence the damage mechanism of the material.