Solid state reaction was applied as a simple and cheap process for synthesizing Ce0.9Cu0.1O1.9 mixed oxide by milling of CuO and CeO2. Response surface methodology (RSM) technique was used to design a three-levels-two-factors (milling times of 20, 95 and 170 min and milling speeds of 100, 150 and 200 rpm) to investigate and optimize CO conversion in medium temperature shift (MTS) reaction (300-390 degrees C). According to contour plots, the interaction between parameters (time and speed of) is so important. Determined optimal values of milling time and speed which lead to conversions of 34.9, 47.2, 61.4 and 71.7% at 300, 330, 360 and 390 degrees C, are 120 min and 162 rpm, respectively. X-ray diffraction (XRD) analysis showed that the trend of crystalline size versus milling speed is different for each milling time: constant for low times, with a maximum for medium times and incremental for high times. Increasing milling time and speed leads to BET surface area decrease and Cu-Ce spices formation which causes better reducibility (TPR) and larger particles (SEM). It was determined that mild values of time and speed (95 min and 150 rpm) lead to the best catalytic performance with good catalytic stability. (C) 2018 Hydrogen Energy Publications LLC. Published by Elsevier Ltd. All rights reserved.