Pursuing sustainable and environmentally friendly cooling solutions has underscored the significance of exploring alternative refrigerants in various industrial applications. Previous publications showed that high-speed screw spindle compressors are a viable solution for water vapor (R 718) applications. This paper introduces a design optimization strategy targeting the efficiency enhancement and mechanical stress mitigation of high-speed screw spindle compressors. As rotational speed increases, so does volume flow and efficiency, but mechanical stress becomes a challenge, especially on the root diameter of the spindle teeth. The research investigates this trade-off and proposes a design that allows higher speeds while alleviating mechanical limitations, increasing its mechanical safety. The proposed design optimization is validated through analytical calculations and thorough FEM simulations, displaying substantial efficiency improvements and volumetric flow rate increments at elevated speeds. The observed outcomes underline the approach's potential in facilitating efficient, high-speed screw spindle compressors.