The hydrodynamic resistance in a biocatalyst particle fixed bed reactor was studied. The biocatalyst used was immobilized glucose isomerase supported by an organic carrier composed of cross-linked proteins. The bed structural deterioration caused by compression-enhanced particle fragmentation and washing-out was considered. The resistance functions (friction factor vs. Re) for four different cases of polydisperse material with increasing spread of the size distribution, corresponding to different extents of particle destruction, were evaluated. The experiments were repeated with three different values of the bed compression, corresponding to different sample positions in the large-scale isomerization column. The relationships obtained exhibited slopes slightly greater than those predicted theoretically for stable packings. This effect can be explained by the increased irregularity of voids due to bed degradation, accompanied by the formation of hollow spaces and sudden changes in the cross-section of the channels. A semiempirical correlation recommended by Reichelt was found to represent the experimental data well for the practically important region of Re > 0.5.