Fixed-bed reactors for liquid hot water pretreatment (LHW) are a promising approach for profitable lignocellulose pretreatment. The flow-through treatment in a tightly packed biomass bed enables high solids loadings and recovery of a considerable hemicellulose oligomer fraction in the liquid product stream. However, the dense biomass packing, as well as the elevated hydrolysate viscosity, cause a significant pressure drop over the bed length, which is likely to compress the fixed-bed irreversibly. This is expected to lead to fluid maldistribution or in the worst case to complete blocking of the reactor. Fixed-bed scale-up, in this case, is therefore not possible without a detailed understanding of the processes inside the bed. This work investigates the pressure drop, fixed-bed mechanics, scale-up as well as possible stabilization techniques of a perfused wheat straw bed during LHW pretreatment experimentally and based on a comprehensive process model. The results show that it is possible to predict the behavior of a fixed-bed with changing bed and fluid properties with the developed model, including heat and mass transfer, reaction kinetics as well as fluid mechanics and bed compression at 3 L lab and 40 L pilot scale. Further, it could be shown that the pressure drop and bed compressibility strongly limit the scale-up potential of the investigated lignocellulose fixed-bed and elaborate stabilization internals are required.