Minimum spin-filter fouling and optimum cell retention at high specific perfusion rates are important for efficient operation of a spin-filter based continuous perfusion bioreactor. We examined the effect of operation conditions and spin-filter configuration on the performance of continous perfusion bioreactors using a perfusion recycle scheme. This study showed that single cell suspensions foul a spin-filter screen, partially but irreversibly, in the early stages of the bioreactor run. A high perfusion rate and cell density contribute to screen fouling, while an increase in rotational velocity and screen surface area per reactor volume reduce screen fouling. An empirical model was developed to describe the effects of these parameters on the perfusion capacity of a spin-filter. Examination of screen samples by scanning electron microscopy confirmed that partial screen fouling occurs at relatively early stages of fermentation. Once the initial partial screen fouling has occurred, further fouling continues slowly due to cell growth on the screen surface, and this gradually leads to the overflow state. The rate of this gradual fouling phase probably depends upon the number of cells deposited on the screen surface during the initial partial fouling. The usefulness of this model was confirmed by successful scale-up of high-cell-density (>10 × 106/mL) long-term (>30 days) continuous perfusion process for commercial scale production of monoclonal antibodies.