Model simulations can support design and cost calculations for both anaerobic digestion and sidestream treatment in order to evaluate the implementation of innovative thermal hydrolysis technologies in the context of the entire plant. SBR based influent characterization, sludge production calibration, and bench-scale digestion experiments of TH-treated sludge from Blue Plains WWTP have been conducted. In the mesophilic pilot digesters of 15 and 20 days retention time COD-removal efficiencies of 56% and 60%, respectively, have been achieved compared to 50% in the control. The resulting data set has been used to calibrate the introduced model approach: The mathematical model for growth of acetoclastic methanogens considers free ammonia inhibition and limitations of undissociated acetic acid as substrate. The impacts of these two compounds appeared very relevant for high-solids digestion and the model provided better understanding of these process interactions.