Using a modified version of the volume-averaged continuum theory for multiphase processes, theoretical predictions of pressure drop across compressible packed beds of Sepharose Big-Beads SP (Amrad Pharmacia Biotech, Sydney, Australia) are made. Modifications to the volume-averaged continuum theory included an additional term incorporated into governing equations to account for the influence of column diameter and a constitutive function to account for the effect of compressibility on pressure gradient. Theoretical predictions are compared to experimental pressure-drop data. Results indicate the modified volume-averaged continuum theory can provide accurate pressure-drop predictions for Sepharose Big-Beads SP at different bed heights, column diameters, superficial velocities, and fluid viscosity. The influence of column diameter on pressure-drop behavior during scale-up is then examined by comparing theoretical predictions for laboratory and production-scale columns. Predictions demonstrate a significant dependence on column diameter. This result emphasizes the dangers of predicting pressure-drop behavior for compressible chromatography resins in production-scale columns by extrapolation from laboratory-scale pressure-drop data.