Ultrafiltration is an important step in the downstream processing of polysaccharide-based vaccines. The objective of this paper was to examine the ultrafiltration behavior of several native polysaccharide serotypes (Pn3, Pn9V, and Pn14) in different membrane modules. The transmission of Pn9V and Pn14 are governed by concentration polarization effects, with the greatest extent of polarization seen in the stirred cell followed by the hollow fiber module and then the tangential flow filtration (TFF) cassette as expected. In contrast, transmission of the highly charged Pn3 serotype in the hollow fiber and TFF cassette reached a maximum value of only about 20% due to membrane fouling, even though data in the stirred cell showed no effects of fouling on the sieving coefficient under otherwise identical conditions. The high degree of fouling by Pn3 appears to be associated with elongation of this high molecular weight polysaccharide in the high shear environment in the tangential flow modules. Rheological data for Pn3, which was the most highly charged and largest molecular weight polysaccharide examined in this work, showed a high degree of shear-thinning. These results provide important insights into the effects of polarization, fouling, and module design on the ultrafiltration behavior of these important polysaccharides.