Abstract A dynamic mathematical model capable to predict the methane production in an anaerobic completely stirred tank reactor (CSTR), performing the co-digestion of the organic fraction of municipal solid waste (OFMSW) and sewage sludge, is used to assess the effect of the organic loading rate (OLR) and OFMSW particle size on the reactor performances. The model is based on the approach proposed by the IWA Anaerobic Digestion Model no. 1 (ADM1), which has been modified to take into account the peculiarities of a co-digestion process. The main distinctiveness of the proposed model consists in considering two separate influent substrates (i.e. sewage sludge and OFMSW), which are modelled with different biodegradation kinetics. The sewage sludge degradation is modelled according to the ADM1 while a surface based kinetics is used to simulate the OFMSW disintegration process, which depends on particle size distribution (PSD) of the solid waste to be disintegrated. The methane production of a full scale municipal wastewater treatment plant (MWWTP) digester has been evaluated to assess the model capability to estimate the potential energy production under different process conditions. In particular, a sensitivity analysis on two key operational parameters of the CSTR co-digestion process, i.e. OLR and OFMSW particle size, has been carried out. This analysis shows the model suitability to assess the combined effect of such parameters on the digester performances, predicting the process failure occurrence.