The hydrodynamic behaviors of fluid flow through particles bed composed of soft Sepharose gel particles were studied theoretically and experimentally. A number of in situ strengths of single gel particle and inter-particle contact modes among gel particles were explored. Effect of particle deformation due to frictional drag and mass of particles on the reduction of porosity was studied to examine how this variation led to the increase in flow resistance. The expansion of gel particles bed after the release of hydraulic drag force was observed. Theoretical predictions were compared to experimental pressure-drop data obtained by Colby et al. (1996). Results showed that the proposed theory could provide accurate steady-state pressure-drop predictions in gel particles bed composed of soft gel particles at different superficial velocities.