Municipal solid waste (MSW) in landfill bioreactors is subjected to mechanical, biological, and hydrological processes. To understand these processes, four large-scale bioreactor pilots were specifically designed to simulate the behavior of waste in the core of a landfill. Here, the results of two long-term tests that were performed in two compression cells are presented. Mechanical, biochemical, and hydrological parameters were analyzed throughout the experiments. The promising results of this research improve the understanding of biodegradation and its correlation with the hydromechanical behavior of municipal solid waste. In particular, the sensitivity of the biodegradation to leachate injection and the correlation between the biogas flow and vertical settlement were confirmed for wastes with high initial moisture content. The results showed that it is important to consider the potential of different monitoring techniques and the representative volume for the experimental approach. Furthermore, the operational results led to interesting conclusions, especially regarding the addition of moisture to waste, which is a key element for bioreactor landfill operation.