Reactive separation processes were recently proposed for the synthesis of fatty acid methyl esters (FAMEs), most of them making use of solid catalysts thus eliminating all conventional catalyst-related operations, improving process efficiency and reducing energy requirements. Such integrated systems require a stoichiometric reactants ratio in order to achieve complete conversion and high purity products. However, maintaining this ratio can be very difficult in practice, especially when the fatty acids feed composition is not constant in time. This study proposes a novel biodiesel process based on a reactive dividing-wall column (R-DWC) that allows the use of only similar to 15% excess of methanol to completely convert the fatty acids feedstock. FAME are produced as pure bottom product, water as side stream, while the methanol excess is recovered as top distillate and recycled. The design is a challenging global optimization problem with discrete and continuous decision variables. The optimal setup was established by using simulated annealing as optimization method implemented in Matlab, and coupled with rigorous simulations carried out in Aspen Plus. Along with the FAME production, the novel design alternatives allow a fortune to be saved by reducing the energy requirements with over 25% and by using less equipment units than conventional processes. (C) 2012 Elsevier Ltd. All rights reserved.