Al-Si-Cu alloys are the most widely used materials for high-pressure die casting processes. In such alloys, Fe content is generally high to avoid die soldering issues, but it is considered an impurity since it generates acicular intermetallics (β-Fe) which are detrimental to the mechanical behavior of the alloys. Mn and Cr may act as modifiers, leading to the formation of other Fe-bearing particles which are characterized by less harmful morphologies, and which tend to settle on the bottom of furnaces and crucibles (usually referred to as sludge). This work is aimed at evaluating the influence of sludge intermetallics on the fatigue behavior of A380 Al-Si-Cu alloy. Four alloys were produced by adding different Fe, Mn and Cr contents to A380 alloy; samples were remelted by directional solidification equipment to obtain a fixed secondary dendrite arm spacing (SDAS) value (~10 µm), then subjected to hot isostatic pressing (HIP). Rotating bending fatigue tests showed that, at room temperature, sludge particles play a detrimental role on fatigue behavior of T6 alloys, diminishing fatigue strength. At elevated temperatures (200◦C) and after overaging, the influence of sludge is less relevant, probably due to a softening of the α-Al matrix and a reduction of stress concentration related to Fe-bearing intermetallics.