Cast polycrystalline nickel-base superalloys are typically used for critical high temperature aerospace and automotive components, such as turbine blades or turbocharger wheels. These high temperature components can undergo creep damage caused by, e.g., centrifugal forces on the turbine rotor blades, as well as high-cycle fatigue (HCF) from, for instance, vibrations of the rotor blade. Therefore, both, creep resistance and fatigue strength are important mechanical properties of these materials. The study presented here addresses the introduction of creep damage and its influence on the high-cycle fatigue behavior. For this purpose, fatigue specimens of coarse-grained Alloy 247 LC CC blade root material were prestressed on a pneumatic creep test rig to achieve creep-induced microstructural damage. The isothermal 900 °C short-time creep investigations below 1000 h test duration were performed at different tensile stresses which result in different strain rates. After the creep tests, scanning electron- and optical microscopy investigations of metallographic cross section of selected specimens were performed to determine the creep-induced grain boundary damage such as pore count, pore size, and coarsening of the γ' structure. This was followed by uniaxial, stress-controlled isothermal 850 °C high cycle fatigue tests on undamaged and predamaged specimens at a frequency of 10 Hz and a load ratio of R = −1. Subsequently, fractographic and cross section investigations, which provide information on the fatigue cracking, the failure initiating defects, and the pore morphology, were performed. The results of this study show that the degree of creep induced porosity is a dominant structural parameter for the HCF behavior of the investigated nickel-base superalloy.