Biodiesel synthesis over calcium oxide (CaO) catalyst in a packed-microchannel was enhanced by using iso-propanol as co-solvent. The influence of operating conditions on the biodiesel synthesis was studied by applying Box-Behnken design (BBD) with the response surface methodology (RSM). The improved reaction efficiency was associated with the less required residence time of reaction and methanol-to-oil molar ratio. The optimal conditions were found at the residence time of 6.5 min, methanol-to-oil molar ratio of 20:1, and co-solvent amount of 14.5 wt.% providing the purity of methyl esters of 99%. The superior productivity of our reactor with energy saving was also presented. (C) 2017 The Korean Society of Industrial and Engineering Chemistry. Published by Elsevier B.V. All rights reserved.