This study aims to develop an optimal continuous process to produce fatty acid methyl esters (biodiesel) from waste cooking palm oil in a reactive distillation column catalyzed by a heteropolyacid, H 3PW 12O 40·6H 2O. The conventional production of biodiesel in the batch reactor has some disadvantage such as excessive alcohol demand, short catalyst life and high production cost. Reactive distillation combines reaction and separation to simplify the process operation. The reaction catalyzed by H 3PW 12O 40·6H 2O overcomes the neutralization problem that occurs in conventional transesterification of waste cooking oil with high free fatty acid (FFAs) and water content. Response surface methodology (RSM) based on Box-Behnken was used to design the experiment and analyzed four operating parameters: total feed flow, feed temperature, reboiler duty and catalyst concentration. The optimum conditions were determined to be 115.52 (mol/h) total feed flow, 29.11°C feed temperature, 1.22 kW reboiler duty, and 10 catalyst concentration. The optimum and actual WCO conversion was 95.1% and 94.8%, respectively, which shows that the RSM is an accurate method for the current procedure.