Filtration behavior of normal flow membrane filters is often described using models based on the classical filtration blocking laws. However, it has been shown that these models are inadequate when the rate of fouling depends on flow rate, as has been found for sterilizing filtration of some bioprocess fluids. In this study, fouling models that had been previously developed in which blocking and adsorption mechanisms were combined for simulating behavior of filters operated in either constant pressure or constant flow mode, were extended to dual filters operated in series. For filters operated in series at constant inlet pressure, each filter within the filtration train will operate at neither constant pressure nor constant flow, as the filters (typically a prefilter and a final filter) will generally foul at different rates. Fouling models that do not account for the effect of flow rate on fouling rate will therefore not properly simulate series filtration behavior. The model developed here was demonstrated to improve accuracy in predicting bioprocess fluid filtration performance of microfiltration membranes operated in series, from measured performance of each membrane filter operated individually. In addition, the model and developed method allows for rapid and efficient optimization of prefilter to final filter area ratio. (C) 2012 Elsevier B.V. All rights reserved.