The poultry slaughterhouse industry, consumes a large volume of potable water for bird processing and equipment cleaning, which culminates in the generation of high strength poultry slaughterhouse wastewater (PSW). The wastewater contains high concentrations of organic matter, suspended solids, nitrogen and nutrients. Most poultry slaughterhouses in South Africa (SA), discharge their wastewater into the municipal sewer system after primary treatment. Due to its high strength, PSW does not meet SA's industrial discharge standards. Discharge of untreated PSW to the environment raises environmental health concerns due to pollution of local rivers and fresh water sources, leading to odour generation and the spread of diseases. Thus, the development of a suitable wastewater treatment process for safe PSW discharge to the environment is a necessity. In this study, a biological PSW treatment process using an Expanded Granular Sludge Bed (EGSB) was evaluated. Response surface methodology coupled with central composite design was used to optimize the performance of the EGSB reactor. The dependant variable used for optimization was COD removal as a function of two independent variables, hydraulic retention time (HRT) and organic loading rate (OLR). The interactions between HRT, OLR and COD removal were analysed, and a two factorial (2FI) regression was determined as suitable for COD removal modelling. The optimum COD removal of 93% was achieved at an OLR of 2 g-COD/L/d and HRT of 4.8 days. The model correlation coefficient (R2) of 0.980 indicates that it is a good fit and is suitable for predicting the EGSB's COD removal efficiency.