In the present study, we evaluated the feasibility of integrating the Taguchi method and the response surface methodology (RSM) to predict and optimize fermentative hydrogen production of cow manure (CM) slurry, a mixture of CM and tap water that was equivalent to 6% of the volatile solid (VS) content. Batch vial tests were first conducted in accordance with an experimental design using the Taguchi method L-18 orthogonal array that selected the significant influencing factors (temperature and pH) of hydrogen production, and then the RSM with a central composite design was used for the following experiments based on the aforementioned factors. Finally, fermentation experiments in triplicate were carried out in a 2-L semi-continuously stirred tank reactor (semi-CSTR) with a fixed organic loading rate (OLR), solid retention time (SRT) and varying temperatures and pH under a steady-state operation. Through a series of investigations conducted in this study, our experimental data confirmed that the optimal conditions were 60 degrees C with pH 5.20 +/- 0.21, resulting in hydrogen content (HC) of 54.64 +/- 11.45%, volumetric hydrogen production (VHP) of 405.54 +/- 193.61 ml-H-2/l/d, and specific hydrogen yield (SHY) of 10.25 +/- 4.96 ml-H-2/g-VS. This study demonstrates a good performance of the Taguchi method with pretests and the prediction of the response surfaces methodology. The confirmed experimental results show the behavior of anaerobic fermenters' treating in significant factors, which will comply with management strategies for treatment of relative organic wastes in the future. Copyright (c) 2012, Hydrogen Energy Publications, LLC. Published by Elsevier Ltd. All rights reserved.