BACKGROUND: The focus of this paper is the ultrasound-assisted synthesis of caffeic acid phenethyl ester (CAPE) from caffeic acid and phenyl ethanol in a continuous packed-bed bioreactor. Immobilized Novozym (R) 435 (from Candida antarctica) is used as the catalyst. A three-level-three-factor Box-Behnken design and a response surface methodology (RSM) are employed to evaluate the effects of temperature, flow rate, and ultrasonic power on the percentage molar conversion of CAPE. RESULTS: Based on ridge max analysis, it is concluded that the optimum condition for synthesis is reaction temperature 72.66 degrees C, flow rate 0.046 mL min(-1), and ultrasonic power 1.64 W cm(-2). The expected molar conversion value is 97.84%. An experiment performed under these optimal conditions resulted in a molar conversion of 92.11 +/- 0.75%. The enzyme in the bioreactor was found to be stable for at least 6 days. CONCLUSIONS: The lipase-catalyzed synthesis of CAPE by an ultrasound-assisted packed-bed bioreactor uses mild reaction conditions. Enzymatic synthesis of CAPE is suitable for use in the nutraceutical and food production industries. (C) 2011 Society of Chemical Industry