Fc-fusion proteins are an important new class of biotherapeutics; however, there is currently little published data on the behavior of these proteins in downstream processing operations. The objective of this study was to evaluate the ultrafiltration behavior of a highly purified Fe-fusion protein in both citrate/phosphate and histidine buffers over a wide range of protein concentrations. Filtrate flux data were obtained using a Pellicon 3 tangential flow filtration cassette. Results were analyzed using a modified version of a recently developed ultrafiltration model that accounts for the effects of intermolecular interactions on protein mass transfer, suitably extended to include the flux in the pressure-dependent regime. The key parameters in this model were evaluated from independent measurements of the solution viscosity and osmotic pressure for protein concentrations up to 200 g/L. The filtrate flux and maximum achievable protein concentration in the histidine buffer were both significantly lower than the corresponding values in the citrate/phosphate buffer due primarily to the greater viscosity in the histidine buffer. The modified concentration polarization model was in good agreement with filtrate flux data over the full range of protein concentrations in both the pressure-dependent and pressure-independent regime. These results provide important insights into the factors controlling the ultrafiltration behavior of the Fe-fusion protein.