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There has been a long-standing need in the marketplace for the economic production of small lots of components that have complex geometry. A potential solution is additive manufacturing (AM). AM is a manufacturing process that adds material from the bottom up. It has the distinct advantages of low preparation costs and a high geometric creation capability. However, the wide range of industrial processing conditions results in large variations in the fatigue lives of metal components fabricated using AM. One of the main reasons for this variation of fatigue lives is differences in microstructure. Our methodology incorporated a crystal plasticity finite element model (CPFEM) that was able to simulate a stress–strain response based on a set of randomly generated representative volume elements. The main advantage of this approach was that the model determined the elastic constants (<inline-formula><math display="inline"><semantics><mrow><msub><mi>C</mi><mrow><mn>11</mn></mrow></msub></mrow></semantics></math></inline-formula>, <inline-formula><math display="inline"><semantics><mrow><msub><mi>C</mi><mrow><mn>12</mn></mrow></msub></mrow></semantics></math></inline-formula>, and <inline-formula><math display="inline"><semantics><mrow><msub><mi>C</mi><mrow><mn>44</mn></mrow></msub></mrow></semantics></math></inline-formula>), the critical resolved shear stress (<inline-formula><math display="inline"><semantics><mrow><msub><mi>g</mi><mn>0</mn></msub></mrow></semantics></math></inline-formula>), and the strain hardening modulus (<inline-formula><math display="inline"><semantics><mrow><msub><mi>h</mi><mn>0</mn></msub></mrow></semantics></math></inline-formula>) as a function of microstructure. These coefficients were determined based on the stress–strain relationships derived from the tensile test results. By incorporating the effect of microstructure on the elastic constants (<inline-formula><math display="inline"><semantics><mi>C</mi></semantics></math></inline-formula>), the shear stress amplitude (<inline-formula><math display="inline"><semantics><mrow><mfrac><mrow><mo>Δ</mo><mi>τ</mi></mrow><mn>2</mn></mfrac></mrow></semantics></math></inline-formula>) can be computed more accurately. In addition, by considering the effect of microstructure on the critical resolved shear stress (<inline-formula><math display="inline"><semantics><mrow><msub><mi>g</mi><mn>0</mn></msub></mrow></semantics></math></inline-formula>) and the strain hardening modulus (<inline-formula><math display="inline"><semantics><mrow><msub><mi>h</mi><mn>0</mn></msub></mrow></semantics></math></inline-formula>), the localized dislocation slip and plastic slip per cycle (<inline-formula><math display="inline"><semantics><mrow><mfrac><mrow><mo>Δ</mo><msub><mi>γ</mi><mi>p</mi></msub></mrow><mn>2</mn></mfrac></mrow></semantics></math></inline-formula>) can be precisely calculated by CPFEM. This study represents a major advance in fatigue research by modeling the crack initiation life of materials fabricated by AM with different microstructures. It is also a tool for designing laser AM processes that can fabricate components that meet the fatigue requirements of specific applications.