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As being used for structural applications, where a high corrosion resistance is required, the fatigue behavior of duplex stainless steels (DSS) is governed by the partition of cyclic plasticity to the two phases, ferrite and austenite, respectively. Under very high cycle fatigue (VHCF) loading conditions, the heterogeneous distribution of crystallographic misorientations between neighboring grains and phases yields to a pronounced scatter in fatigue life, ranging from 1 million to 1 billion cycles for nearly the same stress amplitude. In addition, the relevant damage mechanisms depend strongly on the atmosphere. Stress corrosion cracking in NaCl-containing atmosphere causes a pronounced decrease in the VHCF life. By means of ultrasonic fatigue testing at 20kHz in combination with high resolution scanning electron microscopy, electron back-scattered diffraction (EBSD), focused ion beam milling (FIB) and synchrotron tomography, the microstructure heterogeneities were quantified and correlated with local fatigue damage. It has been shown that the fatigue process is rather complex, involving redistribution of residual stresses and three-dimensional barrier effects of the various interfaces. The application of a 2D/3D finite element model allows a qualitative prediction of the fatigue-damage process in DSS that is controlled by stochastic local microstructure arrangements.