The combined process efficiency with respect to fermentative hydrogen (H(2)) production and wastewater treatment was evaluated in a series of batch experiments to enumerate the role of selected factors viz., origin of inoculum, pre-treatment, inlet pH and feed composition under anaerobic microenvironment using mixed culture. H(2) production and substrate degradation were found to depend significantly on the selected factors with individual conditions to achieve effective process performance. Significantly diverse operational conditions were observed for both H(2) production and substrate degradation with respect to process efficiency. However, while dealing with H(2) production in association with wastewater treatment, both the parameters are important and balancing the conditions for combined effective performance is critical. Data enveloping analysis (DEA) was applied to evaluate the combined system performance with respect to the two output parameters (H(2) production and substrate degradation) based on relative efficiency. Among various experimental combinations studied, those with untreated anaerobic mixed inoculum under acidophilic conditions (inlet pH 5.5) using simple wastewater as fermentative substrate illustrated combined process efficiency with respect to H(2) production (1.919 mmol H(2)/day; 0.52 mol H(2)/kg COD(R)-day) and substrate degradation (substrate degradation rate, 436 kg COD/m(3)-day). DEA methodology provide the relative efficiency of the system by integrating two output parameters. Further, design of experimental methodology (DOE) by Taguchi approach was applied to enumerate the role of selected factors on the H(2) production and substrate degradation with the final aim of optimizing the process. By adapting the derived optimum conditions, the performance with respect to H(2) production and substrate degradation could be enhanced by three fold. (C) 2008 International Association for Hydrogen Energy. Published by Elsevier Ltd. All rights reserved.