A 1-D model, which neglects radial variations, describes the hydrodynamics of cell-free ultrafiltration hollow-fiber bioreactors (HFBRs) and the transport of high molecular-weight proteins trapped in the extracapillary space (ECS). The profiles of radially-averaged protein concentrations predicted by this model are identical to those obtained using a model with radial variations. The model predictions agree well with axial profiles of bovine serum albumin (BSA) and human transferrin concentrations measured in transient and steady-state experiments. The validated model explores the influence of cell culture operating conditions on HFBR protein transport. Increasing protein loading decreases BSA and transferrin polarization in HFBRs operated with unidirectional lumen flow. A relationship developed predicts the protein loading needed to ensure a nonzero steady-state protein concentration throughout the ECS. This critical protein loading depends only on the lumen pressure drop and the ECS protein osmotic pressure. Periodic reversal of the lumen flow direction also decreases protein polarization. The influence of the flow-direction switching time and membrane permeability on the ECS protein distribution is investigated.