Abstract Flow non-uniformity is a major problem with process chromatography columns which typically have small bed height to diameter ratios. In recent publications, we have proposed box-shaped or cuboid packed-bed devices as efficient alternative to process columns for carrying out high-resolution chromatographic separations. Cuboid packed-bed devices show superior performance in terms of number of theoretical plates, peak width, and peak resolution in multicomponent separations. This paper attempts to explain this based on computational fluid dynamic (CFD) simulations of a cuboid packed-bed device and its equivalent column, i.e. having the same bed height and area of cross-section, and packed with the same chromatographic media. The radial velocity in the column headers decreased very rapidly from the axis to the periphery resulting in significant variation in average velocity along the different flow paths within the column. By contrast, the velocity decreased linearly in the top channel and increased linearly in the bottom channel of a cuboid packed-bed device, resulting in significantly lower variation in the average velocity. Simulated flow-through peaks obtained with the cuboid packed-bed device using dextran as a macromolecular and sodium chloride as a low molecular weight tracer were significantly sharper and more symmetric. Experimental results were in good agreement with those obtained by simulation. Overall, the superior performance of the cuboid packed-bed device could be primarily attributed to the narrower solute residence time distribution resulting from greater flow uniformity.