A novel polyelectrolyte complex (PEC) formed by sodium cellulose sulfate (NaCS) and chitosan was prepared as a candidate material for colon-specific drug delivery system. It was found in experiments that the properties of two raw materials and the process parameters, such as the degree of substitution (DS) and concentration of NaCS, the viscosity and concentration of chitosan, were very important factors on the properties of the final product-NaCS-chitosan-PEC. The preparation of NaCS-chitosan complex was optimized by using response surface methodology to evaluate the effects of these parameters on the degradation properties of NaCS-chitosan in the simulated colonic fluid (SCF). The DS of NaCS was in the range from 0.2 to 0.6, the concentration of NaCS from 2 to 4% (w/v), the viscosity of chitosan from 50 to 550 mPa s, and the concentration of chitosan from 0.5 to 1.5% (w/v). A mathematical model was developed to describe the effect of these parameters and their interactions on the degradation of NaCS-chitosan complex. The optimum operation conditions for preparing NaCS-chitosan complex were determined to DS of NaCS of 0.2, the concentration of NaCS of 4.0% (w/v), chitosan viscosity of 327 mPa s, and the concentration of chitosan 0.5% (w/v), respectively. Validation of experiments with 5 confirmatory runs indicated the high degree of prognostic ability of response surface methodology. (C) 2010 Wiley Periodicals, Inc. J Appl Polym Sci 117:3001-3012,2010