In this study,response surface methodology (RSM) [1] was used to combine with process simulation for complex optimization of operating parameters on a prefractionator distillation column in solvent fermentation process [2].The single-parameter effects of feed position,side stream position and flow rate,overhead reflux rate and cooling temperature on the total solvent content in the bottom residue were investigated by process simulation software PRO/Ⅱ.According to the results of single-parameter simulation,comprehensive optimization was done using RSM method--central composite design (CCD) [3],minimization of total solvent content in the bottom residue as the objective.The best optimized mathematical model was established and the result was verified by both simulation and experiments [4].The results obtained by RSM follows are consistent with those obtained by single-factor simulations and the traditional theories of distillation.And the results obtained by RSM are in good agreement with those of simulation and experiment.This indicates that the RSM approach is applicable in the comprehensive optimization of the operating parameters for complex distillation columns.CCD,which is a commonly used strategy in experimental design,has also been proved usefully in simulation-based optimization.The solution of the RSM is more optimal than those of single-factor optimizations.The mathematical model obtained fits well with the effect of the five parameters on the water content of the bottom.It may be regarded asa method for reference,for operating parameters optimization of distillation system.