Molecular orientation has a significant effect on the material properties of polymers. Preferential orientation of the microstructure (polymer chains or crystallites) in a specific direction or plane often enhances the material properties, especially if the high-strength covalent bonds are primarily exposed to loads instead of the weaker van der Waals bonds. However, the orientation-dependent microstructure and its mechanical behavior is in general well understood by many scientific studies. Isotropic materials are frequently required for an intrinsic material characterization without prevailing processing-induced properties, as is the case for Full Notch Creep Test (FNCT) addressing environmental stress cracking (ESC) in high-density polyethylene (PE-HD). Since ESC is one of the major limiting issues for long-term performance of PE-HD pipes and containers, featuring a production-related preferential orientated microstructure due to extrusion or extrusion blow molding, it is important to investigate the ESC resistance of such anisotropic microstructure. Investigations of slow crack growth (SCG) with respect to the molecular orientation generally obtain a factor of 1.2 up to 4.7 between crack growth perpendicular to the extrusion direction and crack growth parallel to the extrusion direction. Based on FNCT investigations with an aqueous detergent solution as environmental medium, hot pressed sheets with isotropic morphology are compared with extruded sheets from which specimens with different orientation angles are taken. However, the time to failure obtained by FNCT is also significantly influenced by the different cooling conditions under which the final morphology is formed. The tendency of the specimen to fail due to ESC is investigated as a function of environmental medium temperature. Evaluating the affecting parameters in the manufacturing process, the ESC resistance is discussed considering the differences in crystallinity as revealed by thermal analysis.