In this study, the response surface methodology was used to optimize parameters of the diluted hydrochloric acid hydrolysis method, which was adopted to separate the polyester-cotton blend fiber. The four parameters reaction time, mass fraction of hydrochloric acid, reaction temperature and solid-liquid ratio were determined by the single factor experiment as they are significant for the process of separation. By introducing the experiment of four factors on three levels designed by Box-Benhnken central composite method, a quadric polynomial regression model for the fiber weight loss rate was established. And the response surface graphs were plotted to illustrate the optimizing process. The response surface analysis determined that the optimized value of the four parameters were 98 minutes, 10.7%, 96.5 °C and 4.3 g/100ml respectively. Under these conditions, polyester-cotton blend fiber was completely separated.