Two-phase anaerobic systems are being increasingly implemented for the treatment of both sewage sludge and organic fraction of municipal solid waste. Despite the good amount of mathematical models in anaerobic digestion, few have been applied in two-phase systems. In this study, a three-reaction mechanistic model has been developed, implemented and validated by using experimental data from a long-term anaerobic two-phase (TPAD) digester treating sewage sludge. A sensitivity analysis shows that the most influential parameters of the model are the ones related to the hydrolysis reaction and the activity of methanogens in the thermophilic reactor. The calibration procedure highlights a noticeable growth rate of the thermophilic methanogens throughout the evaluation period. Overall, all the measured variables are properly predicted by the model during both the calibration and the cross-validation periods. The model's representation of the organic matter behaviour is quite good. The most important disagreements are observed for the biogas production especially during the validation period. The whole application procedure underlines the ability of the model to properly predict the behaviour of this bioprocess.