Separation efficiency of flat- and domed-roof cyclones was investigated in a polypropylene (PP) production process at 20 bar and 80 °C, using computational fluid dynamics (CFD) coupled with the Reynolds stress model for gas turbulence and a discrete random walk model for particles. The geometry of the domed-roof cyclone was based on a high-efficiency Stairmand cyclone and the ASME standard for high-pressure vessels. The meshing strategy and CFD model validation of the cyclones were performed systematically. At an inlet velocity of 20 m/s and atmospheric pressure, the fractional separation efficiency of the domed-roof cyclone was 1.5% higher than that of the flat-roof cyclone in an air-CaCO3 system for particle sizes ranging from 0.1 to 100 µm. Under the high-pressure operating conditions of the domed-roof cyclone, the diameter (De) of the vortex finder was selected as 40% of the cyclone barrel diameter (D), maintaining its high separation efficiency and moderate pressure drop. The optimized domed-roof cyclone achieved an 8.4% higher mean fractional separation efficiency and a 6.4% lower pressure drop compared to a standard flat-roof cyclone for PP particles from 1 to 40 µm. The CFD result provides a useful guide for designing a high-efficiency domed-roof cyclone at high pressures.