A novel mathematics method was proposed to simulate reactive distillation process, in which, molecule scale, fluid mechanical scale, tray scale and column scale were divided to describe mass transfer, heat transfer, gas-liquid two-phase flow, thermodynamics and reaction kinetics in the reactive distillation column. Removing acetic acid from water by esterifying it with methanol was chosen as a model system. The multi-scale (MS) model was solved by the integration of Aspen Plus with Fluent software. The tray efficiencies were calculated by using computational fluid dynamics (CFD) method considering fluid dynamic effects as well as rigorous mass transfer; then, the calculation results were input into Aspen Plus as parameters to simulate the reactive distillation column. The calculated acetic acid conversion in MS model was lower than that in the typical equilibrium stage model under the same conditions and was closer to the experimental result. Based on those results, the effects of operating parameters on acetic acid conversion were investigated to optimize the process. Finally the reactive distillation column was redesigned using the MS model to gain higher conversion of acetic acid. Crown Copyright (c) 2013 Published by Elsevier B.V. All rights reserved.