Dairy production industry is one of the most polluting industries since it generates large volumes of high-strength wastewater. In this research, we studied the interactive effects of chemical oxygen demand (COD), hydraulic retention time (HRT), and COD/nitrogen ratio (COD/N) on the performance of a hybrid expanded granular sludge bed (EGSB) and fixed-bed (FB) bioreactor treating yogurt effluent was studied. For this purpose, response surface methodology (RSM) was applied to predict the behaviors of the system in term of COD removal and biogas production rate (BPR). RSM showed that the best models for COD removal and biogas production rate were the cubic and quadratic models, respectively. The optimum region of the hybrid EGSB-FB reactor was acquired at influent COD of 11,200 mg/L, HRT of 27 h, and COD/N ratio of 51. These variables resulted in a 90% COD removal efficiency and a 180 mL/h BPR. COD/N ratio (relevant coefficient=4.37) and influent COD (relevant coefficient=29.99) resulted respectively as the most effective parameters on COD removal and BPR. (C) 2017 Institution of Chemical Engineers. Published by Elsevier B.V. All rights reserved.