The aim of this study was to develop and optimize the pH-independent extended-release (ER) formulations of cefpodoxime proxetil (CP) using response surface methodology by employing a 3-factor, 3-level Box-Behnken statistical design. The independent variables studied were the amount of hydroxypropyl methylcellulose (HPMC K4M), sodium alginate (SA) and microcrystalline cellulose (MCC). The drug release percent at 2, 4, 8, 14 and 24 h were the target responses and were restricted to 15-30, 35-55, 55-75, 75-90 and 90-110%, respectively. The response surface methodology and multiple response optimizations utilizing a polynomial equation were used to search for the optimal formulation with a specific release rate at different time intervals. The results showed that the effect of combination of HPMC K4M and SA was the most influencing factor on the drug release from ER matrix tablets. The mechanism of drug release from ER tablets was dependent on the added amount of SA. Validation of the optimization technique demonstrated the reliability of the model. The optimized formulation containing 25% HPMC, 15.14% SA, and 20.14% MCC was prepared according to the software determined levels. DSC and FTIR studies combined with the stability study of the optimized formulation proved the integrity of the developed formulation. The Box-Behnken experimental design facilitated the formulation and optimization of extended release hydrophilic matrix systems of CP in a short period of time and with the fewest number of experiments. (C) 2013 The Institution of Chemical Engineers. Published by Elsevier B.V. All rights reserved.