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The one-dimensional (1D) mathematical model of fixed bed reactor was developed for dimethyl ether (DME) synthesis at pilot-scale (capacity: 25–28 Nm3/h of syngas). The reaction rate, heat, and mass transfer equations were correlated with the effectiveness factor. The simulation results, including the temperature profile, CO conversion, DME selectivity, and DME yield of the outlet, were validated with experimental data. The average error ratios were below 9.3%, 8.1%, 7.8%, and 3.5% for the temperature of the reactor, CO conversion, DME selectivity, and DME yield, respectively. The sensitivity analysis of flow rate, feed pressure, H2:CO ratio, and CO2 mole fraction was investigated to demonstrate the applicability of this model.