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Studies showed that grids are significant to the accuracy of numerical simulation in hypersonic flows, but there is no definite method to determine the magnitudes of grid sizes yet. This paper proposes theoretical guidance for grid size design from the physical phenomena, small-scale structures generated in hypersonic flows with interaction between viscous/non-viscous flows, which can be proved by interaction shear flows (ISF) theory. The small-scale structure's physical scale can be a reference to determine the grid sizes in flow and normal direction for CFD calculation. The results show that the accuracy of numerical simulation is partly related to the grid size, and the better simulation results can be obtained when using grid designed by the small-scale structure of ISF theory. By the guidance, we can determine the magnitudes of grid size directly without refining the grids times to try the best grid size.