Response surface methodology (RSM) with a central composite rotatable design (CCRD) was employed to optimize the process of ultrasound-assisted ultrafiltration (UF) for Radix astragalus mixtures. The effects and mutual interaction of several parameters, namely ultrasonic power, ultrasonic irradiation mode, trans-membrane pressure (TMP) and temperature, on fouling degree (Y 1) and process duration (Y 2) were investigated simultaneously. The analysis of variance (ANOVA) demonstrates that the second order polynomial regression models were appropriate and significant, with R 2 of 0.9820 and 0.9581 for Y 1 and Y 2, respectively. The study also shows that TMP is the most significant factor, followed by the temperature, ultrasonic power and irradiation mode. The desirability function approach was used to find the optimum conditions to minimize fouling degree and process duration simultaneously. The optimum conditions were found to be at ultrasonic power of 120 W, continuous ultrasonic irradiation mode, TMP of 0.60 bar and temperature of 20 °C. The predicted responses are 40.2% for fouling degree and 57 min for process duration, which are in good agreement with the results obtained from the confirmation experiments, valued about 38.5-43% and 53-58 min respectively. The results indicate that the regression models are adequate and RSM is an efficient optimization tool for multi-responses and multi-variables study. ; Department of Applied Biology and Chemical Technology