Equilibrium reactive distillation (RD) process simulation and economic evaluation were carried out for the esterification of complex mixtures of several fatty acids and water (representative of crude bio-oils) with n-butanol using Aspen PLUS process simulator and economic analyzer. Complete design and optimization were carried out using evolutionary techniques from simplest system to the most rigorous one with introduction of intermittent progressive complexity. Prior to distillation design, esterification reaction kinetics and binary/ternary interactions were analyzed using Aspen RGibbs reactor module and Property PLUS, respectively. Simple distillation column was designed and optimized to obtain the initial trial parameters to be used in RD simulation. UNIQUAC is used as base property method and reaction equilibria estimated by minimization of Gibbs free energy. Near atmospheric column pressure, reflux ratio of 0.95, distillate to feed ratio of 0.505 and total 18 stages were found to be optimum based on attainable reaction conversion, ester separation, heat duties, and capital and operating costs. The effects of n-butanol:acid feeding ratio and water percent in bio-oil and their relationship were also analyzed to predict n-butanol requirement. The results of this study, including the optimized parameters, could serve as design platforms for pyrolysis bio-oil upgradation to transportation fuels. (C) 2019 Institution of Chemical Engineers. Published by Elsevier B.V. All rights reserved.