Many industrial components made of cast aluminum alloys are subjected to multiaxial loadings, while most of research on these materials are on uniaxial loading condition. This article investigates the fatigue performance of A356-T6 aluminum alloy produced by high pressure die cast (HPDC) under different loading conditions. In addition to obtaining monotonic and cyclic deformation behaviors, fatigue tests were performed under axial, torsion, in-phase and out-of-phase combined loadings. In order to study the fatigue crack growth mechanism, few tests were also conducted under cyclic torsion with static tension or compression. It was observed that the fatigue cracks in all specimens initiated from defects, mainly porosity, and grew on the plane of maximum principal stress. Smith-Watson-Topper (SWT) damage parameter was used to correlate the fatigue data. The experimental fatigue life data were predicted using small crack growth models and from the crack initiating defect on the fracture surfaces. The fatigue lives under different loading conditions were also predicted using the maximum defect size estimated by extreme value statistics. Very good agreements with the experimental lives under different loading conditions were obtained.